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N6-methyladenosine (m6A) modification plays an important role in RNA molecular functions, therefore affecting the initiation and development of hepatocellular carcinoma (HCC). Herein, multiple datasets were applied to conduct a comprehensive analysis of DEGs within HCC and the analysis revealed significant dysregulation of numerous genes. Functional and signaling pathway enrichment analyses were performed. Further, TP53RK binding protein (TPRKB) emerged as a significant factor, exhibiting high expression level within HCC tissue samples and cells which could predict HCC patients' poor OS. Knockdown investigations of TPRKB in vitro demonstrated the effect of TPRKB knockdown on attenuating the aggressiveness of HCC cells by suppressing the viability, colony formation, invasive ability, and migratory ability, inducing cell cycle arrest, and facilitating the apoptosis of HCC cells. Investigations in vivo revealed that TPRKB knockdown significantly suppressed tumor growth in mice model. Additionally, the study identified methyltransferase 5, N6-adenosine (METTL5) as a potential regulator of TPRKB expression via m6A modification, positively regulating TPRKB expression by enhancing TPRKB mRNA stability. The dynamic effects of METTL5 and TPRKB upon the phenotypes of HCC cells further confirmed that TPRKB overexpression partially abolished the anti-cancer effects of METTL5 knockdown upon the aggressiveness of HCC cells. Conclusively, our findings uncover that TPRKB, significantly overexpressed in HCC, exerts a critical effect on promoting tumor aggressiveness, and its expression shows to be positively regulated by METTL5 via m6A methylation. These insights deepen the understanding of HCC pathogenesis and open new avenues for targeted therapies, highlighting that METTL5-TPRKB axis is an underlying new therapeutic target in HCC management.
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BACKGROUND: Circular RNAs are enriched in cardiac tissue and play important roles in the pathogenesis of heart diseases. In this study, we aimed to investigate the regulatory mechanism of a conserved heart-enriched circRNA, circPan3, in cardiac hypertrophy. METHODS: Cardiac hypertrophy was induced by isoproterenol. The progression of cardiomyocyte hypertrophy was assessed by sarcomere organization staining, cell surface area measurement, and expression levels of cardiac hypertrophy markers. RNA interactions were detected by RNA pull-down assays, and methylated RNA immunoprecipitation was used to detect m6A level. RESULTS: The expression of circPan3 was downregulated in an isoproterenol-induced cardiac hypertrophy model. Forced expression of circPan3 attenuated cardiomyocyte hypertrophy, while inhibition of circPan3 aggravated cardiomyocyte hypertrophy. Mechanistically, circPan3 was an endogenous sponge of miR-320-3p without affecting miR-320-3p levels. It elevated the expression of HSP20 by endogenously interacting with miR-320-3p. In addition, circPan3 was N6-methylated. Stimulation by isoproterenol downregulated the m6A eraser ALKBH5, resulting in N6-methylation and destabilization of circPan3. CONCLUSIONS: Our research is the first to report that circPan3 has an antihypertrophic effect in cardiomyocytes and revealed a novel circPan3-modulated signalling pathway involved in cardiac hypertrophy. CircPan3 inhibits cardiac hypertrophy by targeting the miR-320-3p/HSP20 axis and is regulated by ALKBH5-mediated N6-methylation. This pathway could provide potential therapeutic targets for cardiac hypertrophy.
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MicroRNAs , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Isoproterenol , Cardiomegalia/genética , Cardiomegalia/patologia , Miócitos Cardíacos/metabolismoRESUMO
Kawasaki disease (KD) is an acute self-limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high-throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD.
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MicroRNAs , Síndrome de Linfonodos Mucocutâneos , RNA Longo não Codificante , Criança , Humanos , MicroRNAs/genética , Síndrome de Linfonodos Mucocutâneos/genética , RNA Circular , RNA Longo não Codificante/genética , RNA não Traduzido/genéticaRESUMO
OBJECTIVE: To elucidate the underlying mechanism by which the proliferation and migration abilities of human umbilical cord mesenchymal stem cells (hUC-MSCs) determine their therapeutic efficacy in rheumatoid arthritis treatment. METHODS: The DBA/1J mice were utilized to establish a collagen-induced RA (CIA) mouse model and to validate the therapeutic efficacy of hUC-MSCs transfected with CD151 siRNA. RNA-seq, QT-PCR and western blotting were utilized to evaluate the mRNA and protein levels of the PI3K/AKT pathway, respectively. RESULTS: IFN-γ significantly enhanced the proliferation and migration abilities of hUC-MSCs, up-regulating the expression of CD151, a gene related to cell proliferation and migration. Effective inhibition of this effect was achieved through CD151 siRNA treatment. However, IFN-γ did not affect hUC-MSCs differentiation or changes in cell surface markers. Additionally, transplantation of CD151-interfered hUC-MSCs (siRNA-CD151-hUC-MSCs) resulted in decreased colonization in the toes of CIA mice and worse therapeutic effects compared to empty vector treatment (siRNA-NC-hUC-MSCs). CONCLUSION: IFN-γ facilitates the proliferation and migration of hUC-MSCs through the CD151/PI3K/AKT pathway. The therapeutic efficacy of siRNA-CD151-hUC-MSCs was found to be inferior to that of siRNA-NC-hUC-MSCs.
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Artrite Reumatoide , Movimento Celular , Proliferação de Células , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Camundongos Endogâmicos DBA , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Artrite Reumatoide/terapia , Artrite Reumatoide/metabolismo , Camundongos , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Interferon gama/metabolismo , Cordão Umbilical/citologia , Artrite Experimental/terapia , Artrite Experimental/metabolismo , MasculinoRESUMO
Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.
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Antígeno B7-H1 , Imunomodulação , Células-Tronco Mesenquimais , Humanos , Antígeno B7-H1/metabolismo , Células-Tronco Mesenquimais/imunologia , Linfócitos T/metabolismoRESUMO
Amyotrophic lateral sclerosis, a fatal neurodegeneration disease affecting motor neurons in the brain and spinal cord, is difficult to diagnose and treat. The objective of this study is to identify novel candidate genes related to ALS. Transcriptome-wide association study of ALS was conducted by integrating the genome-wide association study summary data (including 1234 ALS patients and 2850 controls) and pre-computed gene expression weights of different tissues. The ALS-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the mRNA expression profiles of the sporadic ALS. Functional enrichment and annotation analysis of identified genes were performed by an R package and the functional mapping and annotation software. TWAS identified 761 significant genes (PTWAS < 0.05), 627 Gene ontology terms, and 8 Kyoto Encyclopedia of Genes and Genomes pathways for ALS, such as C9orf72, with three expression quantitative trait loci were found significantly: rs2453554 (PTWAS CBRS = 4.68 × 10-10, PTWAS CBRS = 2.54 × 10-9), rs10967976 (PTWAS CBRS = 7.85 × 10-10, PTWAS CBRS = 8.91 × 10-9, PTWAS CBRS = 1.49 × 10-7, PTWAS CBRS = 5.59 × 10-7), rs3849946 (PTWAS CBRS = 7.69 × 10-4, PTWAS YBL = 4.02 × 10-2), Mitochondrion (Padj = 4.22 × 10-16), and Cell cycle (Padj = 2.04 × 10-3). Moreover, 107 common genes, 4 KEGG pathways and 41 GO terms were detected by integrating mRNA expression profiles of sALS, such as CPVL (FC = 2.06, PmRNA = 6.99 × 10-6, PTWAS CBR = 2.88 × 10-2, PTWAS CBR = 4.37 × 10-2), Pyrimidine Metabolism (Padj = 2.43 × 10-2), and Cell Activation (Padj = 5.54 × 10-3). Multiple candidate genes and pathways were detected for ALS. Our findings may provide novel clues for understanding the genetic mechanism of ALS.
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Esclerose Lateral Amiotrófica , Transcriptoma , Humanos , Transcriptoma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Esclerose Lateral Amiotrófica/genética , Predisposição Genética para Doença , Locos de Características QuantitativasRESUMO
PURPOSE: Surgical meshes are often used in retro-pectoral implant-based breast reconstruction (IBBR) to improve lower pole expansion. However, using of surgical meshes is associated with increased complications and costs. To solve this problem, we have adopted a modified fascia-based IBBR technique using fasciae of pectoral major, serratus anterior, and external oblique muscles to form a sling covering the lower pole of prosthesis since 2014. METHODS: Data of 788 retro-pectoral IBBR cases, including 250 fascia-based IBBR cases (fascial group) and 538 traditional IBBR cases (control group), treated between 2014 and 2019 were retrospectively analyzed. The surgical outcomes of the fascial and control group were compared. The primary endpoint was the rate of post-operative complications requiring interventions. The secondary endpoint was the rate of explantation. The exploratory endpoint was the time from surgery to complication and explantation. RESULTS: The fascial group had significantly lower rates of developing major post-operative complications (1.2 vs. 6.1%, p = 0.002) and losing prostheses (1.2 vs. 4.3%, p = 0.025), as compared with the control group. The median time from surgery to complication and explantation were 61 (range, 35-115) days and 92 (range, 77-134) days for the fascial group and 35 (range, 6-239) days and 63 (range, 23-483) days for the control group, respectively. CONCLUSION: Fascia-based IBBR technique had low rates of major post-operative complications and explantation. Fascia-based IBBR technique could be considered as an alternative reconstruction method in properly selected patients.
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Implante Mamário , Implantes de Mama , Neoplasias da Mama , Mamoplastia , Humanos , Feminino , Mastectomia/efeitos adversos , Mastectomia/métodos , Neoplasias da Mama/cirurgia , Neoplasias da Mama/complicações , Estudos Retrospectivos , Telas Cirúrgicas/efeitos adversos , Implantes de Mama/efeitos adversos , Resultado do Tratamento , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Implante Mamário/efeitos adversos , Implante Mamário/métodosRESUMO
As flexible wearable devices, hydrogel sensors have attracted extensive attention in the field of soft electronics. However, the application or long-term stability of conventional hydrogels at extreme temperatures remains a challenge due to the presence of water. Antifreezing and antidrying ionic conductive organohydrogels were prepared using cellulose nanocrystals and gelatin as raw materials, and the hydrogels were prepared in a water/glycerol binary solvent by a one-pot method. The prepared hydrogels were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The mechanical properties, electrical conductivity, and sensing properties of the hydrogels were studied by means of a universal material testing machine and LCR digital bridge. The results show that the ionic conductive hydrogel exhibits high stretchability (elongation at break, 584.35%) and firmness (up to 0.16 MPa). As the binary solvent easily forms strong hydrogen bonds with water molecules, experiments show that the organohydrogels exhibit excellent freezing and drying (7 days). The organohydrogels maintain conductivity and stable sensitivity at a temperature range (-50 °C-50 °C) and after long-term storage (7 days). Moreover, the organohydrogel-based wearable sensors with a gauge factor of 6.47 (strain, 0-400%) could detect human motions. Therefore, multifunctional organohydrogel wearable sensors with antifreezing and antidrying properties have promising potential for human body monitoring under a broad range of environmental conditions.
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Pre-B-cell leukaemia transcription factor (PBX) proteins are a subfamily of evolutionarily conserved, atypical homeodomain transcription factors that belong to the superfamily of three amino acid loop extension (TALE) homeodomain proteins. Members of the PBX family play crucial roles in regulating multiple pathophysiological processes, such as the development of organs, congenital cardiac defects and carcinogenesis. The dysregulation of PBXs has been shown to be closely associated with many diseases, particularly cancer. However, the detailed mechanisms of PBX dysregulation in cancer progression are still inconclusive. In this review, we summarize the recent advances in the structures, functions and regulatory mechanisms of PBXs, and discuss their underlying mechanisms in cancer progression. We also highlight the great potential of PBXs as biomarkers for the early diagnosis and prognostic evaluation of cancer as well as their therapeutic applications. The information reviewed here may expand researchers' understanding of PBXs and could strengthen the clinical implication of PBXs in cancer treatment.
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Proteínas de Homeodomínio , Neoplasias , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Neoplasias/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B , Fatores de Transcrição/metabolismoRESUMO
Neuroimaging studies have suggested that the medial prefrontal cortex (mPFC) is a key brain region for social feedback processing, but previous findings are largely based on correlational approaches. In this study, we use the deep transcranial magnetic stimulation (dTMS) to manipulate mPFC activity, then investigate participants' behavioral performance and event-related potentials (ERPs) during the Social Judgment Paradigm. A between-subject design was applied, such that both the active dTMS group and the sham group consisted of 30 participants. We found that the sham group was more likely to predict that they would be socially accepted (rather than rejected) by peers, but the same was not true in the active group. Additionally, this study is the first one to observe ERP signal changes in response to dTMS manipulation. ERP results show that both the expectation stage and the experience stage of social feedback processing were modulated by dTMS: (1) at the expectation stage, the P1 component was smaller in the active group than the sham group, while the stimulus-preceding negativity showed a stronger differentiating effect between positive and negative prediction in the sham group than the active group; (2) at the experience stage, the sensitivity of the late positive potential to the valence and predictability of social feedback was stronger in the sham group than the active group. These results improve our understanding about the relationship between the mPFC and social feedback processing.
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Julgamento/fisiologia , Córtex Pré-Frontal/fisiologia , Estimulação Magnética Transcraniana/métodos , Potenciais Evocados , Retroalimentação , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Continual expression of PD-L1 in tumor cells is critical for tumor immune escape and host T cell exhaustion, however, knowledge on its clinical benefits through inhibition is limited in breast cancer. N6-methyladenosine (m6A) plays a crucial role in multiple biological activities. Our study aimed to investigate the regulatory role of the m6A modification in PD-L1 expression and immune surveillance in breast cancer. METHODS: MeRIP-seq and epitranscriptomic microarray identified that PD-L1 is the downstream target of METTL3. MeRIP-qPCR, absolute quantification of m6A modification assay, and RIP-qPCR were used to examine the molecular mechanism underlying METTL3/m6A/IGF2BP3 signaling axis in PD-L1 expression. B-NDG and BALB/c mice were used to construct xenograft tumor models to verify the phenotypes upon METTL3 and IGF2BP3 silencing. In addition, breast cancer tissue microarray was used to analyze the correlation between PD-L1 and METTL3 or IGF2BP3 expression. RESULTS: We identified that PD-L1 was a downstream target of METTL3-mediated m6A modification in breast cancer cells. METTL3 knockdown significantly abolished m6A modification and reduced stabilization of PD-L1 mRNA. Additionally, METTL3-mediated PD-L1 mRNA activation was m6A-IGF2BP3-dependent. Moreover, inhibition of METTL3 or IGF2BP3 enhanced anti-tumor immunity through PD-L1-mediated T cell activation, exhaustion, and infiltration both in vitro and in vivo. PD-L1 expression was also positively correlated with METTL3 and IGF2BP3 expression in breast cancer tissues. CONCLUSION: Our study suggested that METTL3 could post-transcriptionally upregulate PD-L1 expression in an m6A-IGF2BP3-dependent manner to further promote stabilization of PD-L1 mRNA, which may have important implications for new and efficient therapeutic strategies in the tumor immunotherapy.
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Antígeno B7-H1 , Neoplasias da Mama , Metiltransferases , RNA Mensageiro , Adenosina/análogos & derivados , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Feminino , Xenoenxertos , Humanos , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA , Transdução de SinaisRESUMO
Cancer is a leading disease-related cause of death worldwide. Despite advances in therapeutic interventions, cancer remains a major global public health problem. Cancer pathogenesis is extremely intricate and largely unknown. Fas-associated protein with death domain (FADD) was initially identified as an adaptor protein for death receptor-mediated extrinsic apoptosis. Recent evidence suggests that FADD plays a vital role in non-apoptotic cellular processes, such as proliferation, autophagy, and necroptosis. FADD expression and activity of are modulated by a complicated network of processes, such as DNA methylation, non-coding RNA, and post-translational modification. FADD dysregulation has been shown to be closely associated with the pathogenesis of numerous types of cancer. However, the detailed mechanisms of FADD dysregulation involved in cancer progression are still not fully understood. This review mainly summarizes recent findings on the structure, functions, and regulatory mechanisms of FADD and focuses on its role in cancer progression. The clinical implications of FADD as a biomarker and therapeutic target for cancer patients are also discussed. The information reviewed herein may expand researchers' understanding of FADD and contribute to the development of FADD-based therapeutic strategies for cancer patients.
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Apoptose , Neoplasias , Humanos , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Apoptose/genética , Processos Neoplásicos , Neoplasias/genética , Transdução de SinaisRESUMO
Fe-N-C single-atom catalysts (SACs) are emerging as a promising class of electrocatalysts for the oxygen reduction reaction (ORR) to replace Pt-based catalysts. However, due to the limited loading of Fe for SACs and the inaccessibility of internal active sites, only a small portion of the sites near the external surface are able to contribute to the ORR activity. Here, this work reports a metal-organic framework-derived Fe-N-C SAC with a hierarchically porous and concave nanoarchitecture prepared through a facile but effective strategy, which exhibits superior electrocatalytic ORR activity with a half-wave potential of 0.926 V (vs RHE) in alkaline media and 0.8 V (vs RHE) in acidic media while maintaining excellent stability. The superior ORR activity of the as-designed catalyst stems from the unique architecture, where the hierarchically porous architecture contains micropores as Fe SAC anchoring sites, meso-/macro-pores as accessible channels, and concave shell for increasing external surface area. The unique architecture has dramatically enhanced the utilization of previously blocked internal active sites, as confirmed by a high turnover frequency of 3.37 s-1 and operando X-ray absorption spectroscopy analysis with a distinct shift of adsorption edge.
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BACKGROUND: Abnormal processing of social feedback is an important contributor to social dysfunction in depression, however the exact mechanisms remain unclear. One important factor may be the extent to which social processing depends on expectations, in particular whether social feedback confirms or violates expectations. METHODS: To answer this question, we studied behavioral and brain responses during the evaluative processing of social feedback in 25 individuals with subthreshold depression (SD) and 25 healthy controls (HCs). Participants completed a Social Judgment Task in which they first indicated expectation about whether a peer would like them or not, and then received peer's feedback indicating acceptance or rejection. RESULTS: Individuals with SD who reported greater depressive symptoms gave fewer positive expectations. Compared to HCs, individuals with SD showed reduced activation in the medial prefrontal cortex when expecting positive feedback. They also exhibited increased dorsal anterior cingulate cortex after receipt of unexpected social rejection, and reduced ventral striatum activity after receipt of unexpected social acceptance. CONCLUSIONS: The observed alternations are specific to unexpected social feedback processing and highlight an important role of expectancy violation in the brain dysfunction of social feedback perception and evaluation in individuals at risk for depression.
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Depressão , Julgamento , Humanos , Retroalimentação , Julgamento/fisiologia , Giro do Cíngulo , Percepção SocialRESUMO
In dealing with the COVID-19 pandemic, government officials often encounter two concurrent concerns: they have to enforce necessary public health and safety measures to manage COVID-19. Meanwhile, they also have to mitigate conspiracy beliefs about COVID-19. To shed light on these issues, we conducted two studies to investigate national identity certainty (i.e., the extent to which people are certain about their national identity) as a predictor of (a) support for restrictive measures to curtail COVID-19 and (b) conspiracy beliefs about an outgroup as the culprit of COVID-19. Study 1 was a three-week longitudinal study (N = 301) where we investigated the relationships both on a between-person level (differences between individuals) and on a within-person level (week-by-week fluctuations of the same individual). We found that individual differences in national identity certainty predicted increased support for restrictive measures and increased outgroup conspiracy beliefs. These relationships emerged, even when we controlled for national identity positivity, that is, the extent to which people see their national identity in positive light. In Study 2 (N = 316), we used a cross-sectional correlational design and replicated the findings of Study 1. Moreover, we found that the relationships were explained by distinct threat perceptions: realistic threat explained the increased support for restrictive measures, whereas symbolic threat explained the increased outgroup conspiracy beliefs. Overall, our findings suggest that support for restrictive measures and outgroup conspiracy beliefs can be seen as attempts of people high in national identity certainty to address the distinct threats of COVID-19.
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OBJECTIVES: Platelet-to-lymphocyte ratio (PLR) has recently been investigated as a new inflammatory marker in many inflammatory diseases, including systemic lupus erythematosus and immunoglobulin A vasculitis. However, there were very few reports regarding the clinical role of PLR in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. This study was thus undertaken to investigate the relationship between inflammatory response and disease activity in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis. Furthermore, we evaluated whether PLR predicts the progression of end stage of renal disease (ESRD) and all-cause mortality. METHODS: The clinical, laboratory and pathological data, and the outcomes of MPO-ANCA associated vasculitis patients were collected. The Spearman correlation coefficient was computed to examine the association between 2 continuous variables. Cox regression analysis was used to estimate the association between PLR and ESRD or all-cause mortality. RESULTS: A total of 190 consecutive patients with MPO-ANCA associated vasculitis were included in this study. Baseline PLR was positively correlated with CRP (r=0.333, P<0.001) and ESR (r=0.218, P=0.003). PLR had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients having PLR≥330 exhibited better cumulative renal survival rates than those having PLR<330 (P=0.017). However, there was no significant difference in the cumulative patient survival rates between patients with PLR≥330 and those with PLR<330 at diagnosis (P>0.05). In multivariate analysis, PLR is associated with the decreased risk of ESRD (P=0.038, HR=0.518, 95% CI 0.278 to 0.963). We did not find an association between PLR with all-cause mortality using multivariate analysis (HR=1.081, 95% CI 0.591 to 1.976, P=0.801). CONCLUSIONS: PLR is positively correlated with CRP and ESR. Furthermore, PLR may independently predict the risk of ESRD.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Falência Renal Crônica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/análise , China/epidemiologia , Humanos , Falência Renal Crônica/complicações , Linfócitos , Peroxidase , Estudos RetrospectivosRESUMO
Immune paralysis is a protracted state of immune suppression following the early/acute inflammatory phase of sepsis. CD11b+ Gr-1+ cells induced during sepsis are heterogeneous myeloid-derived cells (MDCs). This study investigated the contribution of MDCs to immune paralysis. Treatment of mice with zymosan (ZM) induced a marked increase in the total number of splenocytes with an increase in the proportion of Gr-1hi cells and a decrease in the proportion of T cells on day 7; levels of these cells eventually return to levels similar to those of control mice on day 21. T-cell activation and gamma interferon (IFN-γ) expression by CD8+ T cells were clearly impaired in ZM-treated mice on day 21 (d21-ZM mice). Gr-1hi cells showed a CD11b+ Ly6Ghi polymorphonuclear phenotype. Injection of lipopolysaccharide (LPS) into d21-ZM mice impaired interleukin 6 (IL-6) production in serum, accompanied by accumulation of CD11b+ Gr-1hi cells in the peripheral blood. Transfer of Gr-1hi cells from d21-ZM mice into intact mice impaired IL-6 production, but similar transfer of Gr-1hi cells from PD-1/PD-L1-deficient d21-ZM mice showed no such suppressive effect. Conversely, either depletion of Gr-1hi cells by treatment with anti-Gr-1 monoclonal antibody (MAb) or neutralization of the PD-1/PD-L1 pathway by anti-PD-1 and anti-PD-L1 MAbs during the induction phase of sepsis ameliorated ZM-induced immune suppression. Our results suggest that the PD-1/PD-L1-mediated generation of Gr-1hi cells in the early phase of sepsis is required for the late phase of immune paralysis.
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Antígeno B7-H1/metabolismo , Imunomodulação , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Imunofenotipagem , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Sepse/etiologia , Sepse/metabolismo , Baço/citologia , Baço/imunologia , Baço/metabolismoRESUMO
Gastric cancer (GC) is one of the most common malignant tumors in China and the third leading cause of cancer-related death. Parkin has been shown to be a tumor suppressor in a variety of malignancies, including GC. However, the mechanism of Parkin in GC remains unclear. In this study, the low expression of Parkin in GC cells and patient tumor tissues was observed, and Parkin inhibited proliferation and migration of GC cells. Additionally, doxorubicin (DOX) upregulated the expression of Parkin and promoted its anticancer effect. Forkhead box O3 (FOXO3a) is a crucial transcription factor that involves in the regulation of cancer cell proliferation, apoptosis, and metabolism. Here, we found that FOXO3a inhibits cell proliferation, migration, and promotes apoptosis in GC by regulating Parkin expression at the transcriptional level. In addition, Parkin inhibited cell proliferation, migration, and promoted apoptosis by inhibiting ATP-binding box protein E1 (ABCE1) expression. In summary, our results demonstrated a new regulatory axis of FOXO3a-Parkin-ABCE1 that modulated GC cell proliferation, migration, and apoptosis, and it can serve as a potential therapeutic target in GC.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteína Forkhead Box O3/metabolismo , Neoplasias Gástricas/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Antibióticos Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Doxorrubicina/farmacologia , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
Sepsis, which is characterized by multiple organ dysfunctions as a result of an unbalanced host-inflammatory response to pathogens, is potentially a life-threatening condition and a major cause of death in the intensive care units (ICUs). However, effective treatment or intervention to prevent sepsis-associated lethality is still lacking. Human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation has been shown to have potent immunomodulatory properties and improve tissue repair yet lacks direct antibacterial and endotoxin clearance activities. In this study, we engineered hUC-MSCs to express a broad-spectrum antibacterial fusion peptide containing BPI21 and LL-37 (named BPI21/LL-37) and confirmed that the BPI21/LL-37 modification did not affect the stemness and immunoregulatory capacities of hUC-MSCs but remarkably, enhanced its antibacterial and toxin-neutralizing activities in vitro. Furthermore, we showed that administration of BPI21/LL-37-engineered hUC-MSCs significantly reduces serum levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6, whereas increases that of IL-10 in cecal ligation and puncture (CLP)-induced sepsis mouse model. Administration of BPI21/LL-37-engineered hUC-MSCs significantly reduced systemic endotoxin (lipopolysaccharide [LPS]) levels and organ bacterial load, ameliorated damage to multiple organs, and improved survival. Taken together, our study demonstrates that BPI21/LL-37-engineered hUC-MSCs might offer a novel therapeutic strategy to prevent or treat sepsis via enhanced antimicrobial and anti-inflammatory properties to preserve organ functions better.
Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteínas Recombinantes de Fusão/farmacologia , Sepse/terapia , Cordão Umbilical/citologia , Animais , Terapia Combinada , Modelos Animais de Doenças , Endotoxinas/imunologia , Engenharia Genética , Humanos , Imunomodulação/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Camundongos , Sepse/etiologia , Sepse/mortalidadeRESUMO
A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.