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Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.
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Replication stress (RS) is a key trait of cancer cells, and a potential actionable target in cancer treatment. Accurate methods to measure RS in tumour samples are currently lacking. DNA fibre analysis has been used as a common technique to measure RS in cell lines. Here, we investigated DNA fibre analysis on fresh breast cancer specimens and correlated DNA replication kinetics to known RS markers and genomic alterations. Fresh, treatment-naïve primary breast cancer samples (n = 74) were subjected to ex vivo DNA fibre analysis to measure DNA replication kinetics. Tumour cell proliferation was confirmed by EdU incorporation and cytokeratin AE1/AE3 (CK) staining. The RS markers phospho-S33-RPA and γH2AX and the RS-inducing proto-oncogenes Cyclin E1 and c-Myc were analysed by immunohistochemistry. Copy number variations (CNVs) were assessed from genome-wide single nucleotide polymorphism (SNP) arrays. We found that the majority of proliferating (EdU-positive) cells in each sample were CK-positive and therefore considered to be tumour cells. DNA fibre lengths varied largely in most tumour samples. The median DNA fibre length showed a significant inverse correlation with pRPA expression (r = -0.29, p = 0.033) but was not correlated with Cyclin E1 or c-Myc expression and global CNVs in this study. Nuclear Cyclin E1 expression showed a positive correlation with pRPA levels (r = 0.481, p < 0.0001), while cytoplasmic Cyclin E1 expression exhibited an inverse association with pRPA expression (r = -0.353, p = 0.002) and a positive association with global CNVs (r = 0.318, p = 0.016). In conclusion, DNA fibre analysis performed with fresh primary breast cancer samples is feasible. Fibre lengths were associated with pRPA expression. Cyclin E1 expression was associated with pRPA and the percentage of CNVs. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias da Mama , Ciclina E , Replicação do DNA , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Ciclina E/genética , Ciclina E/metabolismo , Replicação do DNA/genética , Polimorfismo de Nucleotídeo Único , Proliferação de Células , Variações do Número de Cópias de DNA , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Idoso , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , AdultoRESUMO
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a crucial role in antitumor immunity. However, the role of MIF in influencing the tumor microenvironment (TME) and prognosis of triple-negative breast cancer (TNBC) remains to be elucidated. Using R, we analyzed single-cell RNA sequencing (scRNA-seq) data of 41 567 cells from 10 TNBC tumor samples and spatial transcriptomic data from two patients. Relationships between MIF expression and immune cell infiltration, clinicopathological stage, and survival prognosis were determined using samples from The Cancer Genome Atlas (TCGA) and validated in a clinical cohort using immunohistochemistry. Analysis of scRNA-seq data revealed that MIF secreted by epithelial cells in TNBC patients could regulate the polarization of macrophages into the M2 phenotype, which plays a key role in modulating the TME. Spatial transcriptomic data also showed that epithelial cells (tumor cells) and MIF were proximally located. Analysis of TCGA samples confirmed that tumor tissues of patients with high MIF expression were enriched with M2 macrophages and showed a higher T stage. High MIF expression was significantly associated with poor patient prognosis. Immunohistochemical staining showed high MIF expression was associated with younger patients and worse clinicopathological staging. MIF secreted by epithelial cells may represent a potential biomarker for the diagnosis and prognosis of TNBC and may promote TNBC invasion by remodeling the tumor immune microenvironment.
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Biomarcadores Tumorais , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Macrófagos , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Feminino , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Prognóstico , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão GênicaRESUMO
Scope: The present investigation seeks to illuminate the current state and disparities in the knowledge, attitudes, and practices (KAP) among healthcare professionals regarding the management of lung cancer palliative care (LCPC) in China, while simultaneously assessing the prevalence and context of patient-controlled analgesia (PCA) usage in the management of cancer-related pain. Methods: A total of 2093 healthcare practitioners from 706 hospitals across China completed a structured questionnaire that probed various facets of LCPC management. The questionnaire consisted of seven thematic sections, incorporating chi-square tests and Fisher's exact probabilities to statistically assess the discrepancies in KAP among healthcare professionals across different hospital grades. Ordered data distributions among hospital grades were compared using non-parametric Kruskal-Wallis H and Mann-Whitney U tests. Multiple-choice items were subjected to multiple-response cross-tabulation analysis, while the Spearman rank-order correlation coefficient was employed to gauge potential associations among variables. Results: Around 84.2% of the respondents perceived anti-tumor therapy to be of equal importance to palliative care. Statistically significant differences (χ² = 27.402, P = 0.002) in satisfaction levels were observed, with participants from Tertiary hospitals demonstrating higher satisfaction compared to those from Secondary and Primary hospitals. Pain emerged as the most prevalent symptom necessitating LCPC. Major impediments to LCPC adoption included patients' and families' concerns about the safety of long-term palliative care-related drug use. 31.1% of the respondents cited the most frequent rationale for PCA use as cases involving patients who required systemic administration of large opioid doses or exhibited intolerable adverse reactions to opioids. The principal deterrents against the use of PCA for cancer pain management were (1): apprehension about adverse drug reactions due to overdose (2), concern about the potential for opioid addiction, and (3) the anticipated increase in patients' economic burdens. Over the preceding 24-month period, 33.9% of the surveyed healthcare practitioners reported no engagement in either online or offline LCPC-related training initiatives. Conclusion: This study emphasizes the pressing need for comprehensive training in LCPC among Chinese health personnels, particularly focusing on the effective management of cancer pain symptoms.
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BACKGROUND: EV71 is one of the important pathogens of Hand-foot-and-mouth disease (HFMD), which causes serious neurological symptoms. Several studies have speculated that there will be interaction between 5'UTR and 3D protein. However, whether 5'UTR interacts with the 3D protein in regulating virus replication has not been clarified. METHODS: Four 5'UTR mutation sites (nt88C/T, nt90-102-3C, nt157G/A and nt574T/A) and two 3D protein mutation sites (S37N and R142K) were mutated or co-mutated using virulent strains as templates. The replication of these mutant viruses and their effect on autophagy were determined. RESULTS: 5'UTR single-point mutant strains, except for EGFP-EV71(nt90-102-3C), triggered replication attenuation. The replication ability of them was weaker than that of the parent strain the virulent strain SDLY107 which is the fatal strain that can cause severe neurological complications. While the replication level of the co-mutant strains showed different characteristics. 5 co-mutant strains with interaction were screened: EGFP-EV71(S37N-nt88C/T), EGFP-EV71(S37N-nt574T/A), EGFP-EV71(R142K-nt574T/A), EGFP-EV71(R142K-nt88C/T), and EGFP-EV71(R142K-nt157G/A). The results showed that the high replicative strains significantly promoted the accumulation of autophagosomes in host cells and hindered the degradation of autolysosomes. The low replicative strains had a low ability to regulate the autophagy of host cells. In addition, the high replicative strains also significantly inhibited the phosphorylation of AKT and mTOR. CONCLUSIONS: EV71 5'UTR interacted with the 3D protein during virus replication. The co-mutation of S37N and nt88C/T, S37N and nt574T/ A, R142K and nt574T/A induced incomplete autophagy of host cells and promoted virus replication by inhibiting the autophagy pathway AKT-mTOR. The co-mutation of R142K and nt88C/T, and R142K and nt157G/A significantly reduced the inhibitory effect of EV71 on the AKT-mTOR pathway and reduced the replication ability of the virus.
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Regiões 5' não Traduzidas , Enterovirus Humano A , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Replicação Viral , Enterovirus Humano A/genética , Enterovirus Humano A/fisiologia , Enterovirus Humano A/patogenicidade , Regiões 5' não Traduzidas/genética , Humanos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Autofagia , Animais , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Transdução de Sinais , Chlorocebus aethiops , Mutação , Linhagem Celular , Células VeroRESUMO
Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens, displaying anti-inflammatory, anti-tumor, and antibacterial effects. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis. Nevertheless, the clinical application of oridonin is significantly restricted due to its reproductive toxicity, with the exact mechanism remaining unclear. The aim of this study was to investigate the mechanism of oridonin-induced damage to HTR-8/SVneo cells. Through the integration of epigenetics, proteomics, and metabolomics methodologies, the mechanisms of oridonin-induced reproductive toxicity were discovered and confirmed through fluorescence imaging, RT-qPCR, and Western blotting. Experimental findings indicated that oridonin altered m6A levels, gene and protein expression levels, along with metabolite levels within the cells. Additionally, oridonin triggered oxidative stress and mitochondrial damage, leading to a notable decrease in WNT6, ß-catenin, CLDN1, CCND1, and ZO-1 protein levels. This implied that the inhibition of the Wnt/ß-catenin signaling pathway and disruption of tight junction might be attributed to the cytotoxicity induced by oridonin and mitochondrial dysfunction, ultimately resulting in damage to HTR-8/SVneo cells.
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Overexpression of Cyclin E1 perturbs DNA replication, resulting in DNA lesions and genomic instability. Consequently, Cyclin E1-overexpressing cancer cells increasingly rely on DNA repair, including RAD52-mediated break-induced replication during interphase. We show that not all DNA lesions induced by Cyclin E1 overexpression are resolved during interphase. While DNA lesions upon Cyclin E1 overexpression are induced in S phase, a significant fraction of these lesions is transmitted into mitosis. Cyclin E1 overexpression triggers mitotic DNA synthesis (MiDAS) in a RAD52-dependent fashion. Chemical or genetic inactivation of MiDAS enhances mitotic aberrations and persistent DNA damage. Mitosis-specific degradation of RAD52 prevents Cyclin E1-induced MiDAS and reduces the viability of Cyclin E1-overexpressing cells, underscoring the relevance of RAD52 during mitosis to maintain genomic integrity. Finally, analysis of breast cancer samples reveals a positive correlation between Cyclin E1 amplification and RAD52 expression. These findings demonstrate the importance of suppressing mitotic defects in Cyclin E1-overexpressing cells through RAD52.
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Ciclina E , Instabilidade Genômica , Mitose , Proteínas Oncogênicas , Proteína Rad52 de Recombinação e Reparo de DNA , Humanos , Ciclina E/metabolismo , Ciclina E/genética , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Proteínas Oncogênicas/metabolismo , Proteínas Oncogênicas/genética , Replicação do DNA , Linhagem Celular Tumoral , Dano ao DNA , DNA/metabolismo , DNA/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologiaRESUMO
Background: Inducible co-stimulator (ICOS) shows great potential in the regulation of innate and adaptive immunity. However, previous studies of ICOS have often been limited to one or two levels. Methods: Using the data from the online database, the immunohistochemistry, and enzyme-linked immunosorbent assays, we investigated the role of ICOS / PD-L1 on patients with NSCLC at the mRNA, protein, and serum levels. Results: Our data revealed that unlike most solid tumors, the mRNA expression of ICOS was down-regulated in NSCLC. In addition, our data also showed that mRNA expression levels in ICOS are negatively associated with poor clinicopathologic grading but positively associated with better prognostic outcomes and higher Tregs infiltration level. Immunohistochemistry showed that ICOS correlated negatively with the T stage; while PD-L1 levels correlated positively with the N stage and FOXP3 levels. Serological biomarker analysis showed that patients with NSCLC had lower sICOS levels, which increased significantly post-surgery, and combined sICOS and sPD-L1 diagnosis improved efficacy and accuracy of disease diagnosis. Conclusion: Our findings support that ICOS suggests lower pathological staging and better prognosis. ICOS is a potential diagnostic and prognostic biomarker for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/genética , Prognóstico , Multiômica , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , RNA Mensageiro/genética , Biomarcadores , Proteína Coestimuladora de Linfócitos T Induzíveis/genéticaRESUMO
Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.
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Asma , Interleucina-13 , Animais , Humanos , Camundongos , Sistema y+ de Transporte de Aminoácidos , Asma/genética , Asma/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos BALB C , Ovalbumina/metabolismo , Ovalbumina/uso terapêutico , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/uso terapêutico , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células Th2/metabolismo , Células Th2/patologiaRESUMO
The accurate and timely assessment of lymph node involvement is paramount in the management of patients with malignant tumors, owing to its direct correlation with cancer staging, therapeutic strategy formulation, and prognostication. Dual-energy computed tomography (DECT), as a burgeoning imaging modality, has shown promising results in the diagnosis and prediction of preoperative metastatic lymph nodes in recent years. This article aims to explore the application of DECT in identifying metastatic lymph nodes (LNs) across various cancer types, including but not limited to thyroid carcinoma (focusing on papillary thyroid carcinoma), lung cancer, and colorectal cancer. Through this narrative review, we aim to elucidate the clinical relevance and utility of DECT in the detection and predictive assessment of lymph node metastasis in malignant tumors, thereby contributing to the broader academic discourse in oncologic radiology and diagnostic precision.
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Genomic instability, as caused by oncogene-induced replication stress, can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P < 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P < 0.001) and tumor mutational burden (P < 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.
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Rosacea is a common inflammatory skin disorder mediated by the dysregulation of both keratinocytes and T cells. Here, we report that aquaporin 3 (AQP3), a channel protein that mediates the transport of water/glycerol, was highly expressed in the epidermis and CD4+ T cells of both rosacea patients and experimental mice. Specifically, AQP3 deletion blocked the development of rosacea-like skin inflammation in model mice with LL37-induced rosacea-like disease. We also present mechanistic evidence showing that AQP3 was essential to the activation of NF-κB signaling and subsequent production of disease-characteristic chemokines in keratinocytes. Moreover, we show that AQP3 was upregulated during T cell differentiation and promotes helper T (Th) 17 differentiation possibly via the activation of STAT3 signaling. Our findings reveal that AQP3-mediated activation of NF-κB in keratinocytes and activation of STAT3 in CD4+ T cells acted synergistically and contributed to the inflammation in rosacea.
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Aquaporina 3 , Rosácea , Humanos , Animais , Camundongos , Aquaporina 3/genética , NF-kappa B/metabolismo , Queratinócitos/metabolismo , Pele/metabolismo , Rosácea/metabolismo , Inflamação/metabolismoRESUMO
Euphorbia factor L1 (EFL1) is a kind of lathyrane-type diterpenoid and is isolated from the medical herb Euphorbia lathyris L. (Euphorbiaceae); it has been reported with the toxicity that causes intestinal irritation, but the underlying mechanisms are still obscure. The objective of this study was to assess the EFL1-induced intestinal cytotoxicity in human colon adenocarcinoma Caco-2 cells. The Caco-2 cells were treated with EFL1, and the intracellular calcium ion concentration, mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP), adenosine 5'-triphosphate (ATP) content, ATPase activities, TGF-ß1 concentration, and transepithelial electrical resistance (TEER) were detected. The interaction between EFL1 and the tight junction proteins Occludin, Claudin-4, Tricellulin, ZO-1, JAM-1, and E-cadherin was simulated by molecular docking. The expression of proteins involved in the energy metabolism, the ion transporters and aquaporins, the tight junction, and the F-actin cytoskeleton were detected by Western blotting and cell immunofluorescence. As a result, EFL1 decreased the intracellular Ca2+, MMP, mPTP, ATP content, and ATPase activities in the Caco-2 cells. The AMPK/SIRT1/PGC-1α signaling pathway, which regulates the energy metabolism, was inhibited. The ion transporters NEH and CFTR, as well as the aquaporins in the Caco-2 cells, were decreased. The tight junction proteins were down-regulated, and the integrity of the intestinal barrier was injured; TGF-ß1 was compensatively increased; so, the intestinal permeability was increased and was characterized by decreased TEER. The morphology of the F-actin cytoskeleton was destroyed. These findings indicated that EFL1 caused cytotoxicity in the human intestinal Caco-2 cells through mitochondrial damage, inhibition of the energy metabolism, and suppression of the ion and water molecule transporters, as well as the down-regulation tight junction and cytoskeleton protiens.
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Adenocarcinoma , Aquaporinas , Neoplasias do Colo , Diterpenos , Humanos , Células CACO-2 , Fator de Crescimento Transformador beta1/metabolismo , Simulação de Acoplamento Molecular , Adenocarcinoma/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Diterpenos/farmacologia , Diterpenos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Aquaporinas/metabolismo , Adenosina Trifosfatases/metabolismo , Mucosa Intestinal/metabolismo , PermeabilidadeRESUMO
Rosacea is a chronic inflammatory skin disease originated from damaged skin barrier and innate/adaptive immune dysregulation. Toll-like receptors (TLRs) sense injured skin and initiate downstream inflammatory and immune responses, whose role in rosacea is not fully understood. Here, via RNA-sequencing analysis, we found that the TLR signaling pathway is the top-ranked signaling pathway enriched in rosacea skin lesions, in which TLR7 is highlighted and positively correlated with the inflammation severity of disease. In LL37-induced rosacea-like mouse models, silencing TLR7 prevented the development of rosacea-like skin inflammation. Specifically, we demonstrated that overexpressing TLR7 in keratinocytes stimulates rapamycin-sensitive mTOR complex 1 (mTORC1) pathway via NFκB signaling. Ultimately, TLR7/NFκ B/mTORC1 axis promotes the production of cytokines and chemokines, leading to the migration of CD4+T cells, which are infiltrated in the lesional skin of rosacea. Our report reveals the crucial role of TLR7 in rosacea pathogenesis and indicatesa promising candidate for rosacea treatments.
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Dermatite , Rosácea , Receptor 7 Toll-Like , Animais , Camundongos , Dermatite/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , Rosácea/metabolismo , Pele , Receptor 7 Toll-Like/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismoRESUMO
Purpose: More effective approaches are needed to improve the prognosis of non-small-cell lung cancer (NSCLC) patients. Thus, we used the E-warm model to assess how early integration of interdisciplinary palliative care was related to the quality of life (QoL), psychological functioning, pain management, and nutrition factors of NSCLC patients. Methods: This randomized controlled trial enrolled 280 newly diagnosed NSCLC patients, which were randomly divided (1:1) into combined early palliative care (CEPC) and standard oncological care (SC) groups. At baseline and after 24 weeks, the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale, Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire-9 (PHQ-9) were used to assess QoL and psychological function, respectively. The Numerical Rating Scale (NRS) and Patient-Generated Subjective Global Assessment (PG-SGA) were used to assess cancer patients' pain and nutrition levels. The primary outcome was overall survival (OS). Secondary outcomes comprised changes in the QoL, psychological functioning, pain, and nutrition state. The intention-to-treat method was applied for analysis. This study was registered at www.chictr.org.cn (ChiCTR2200062617). Results: Of the 140 patients enrolled in the CEPC and SC groups, 102 and 82 completed the research. The CEPC group presented higher QoL than the SC group (p < 0.05). Additionally, fewer patients presented depressive symptoms in the CEPC group than in the SC group (p < 0.05), as well as better nutritional status (p = 0.007) and pain management (p = 0.003). Compared to the SC group, CEPC patients had significantly longer OS (20.4 vs. 24.6 months, p = 0.042; HR: 0.19; 95% CI: 0.04-0.85, p = 0.029). Conclusion: With combined early palliative care, NSCLC patients lived longer, had better QoL, were psychologically stable, were in less pain, and were more nutritionally satisfied.
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Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential to improve outcomes for individuals in the advanced stages of CML. A promising therapeutic target is Wilms' tumor 1 (WT1), which is highly expressed in BP-CML cells and plays a crucial role in CML progression. In this study, a chemically synthesized nucleus-targeting WT1 antagonistic peptide termed WIP2W was identified. The therapeutic implications of both the peptide and its micellar formulation, M-WIP2W, were evaluated in WT1+ BP-CML cell lines and in mice. The findings indicate that WIP2W can bind specifically to the WT1 protein, inducing cell cycle arrest and notable cytotoxicity in WT1+ BP-CML cells. Moreover, subcutaneous injections of M-WIP2W were observed to significantly enhance intra-tumoral accumulation and to effectively inhibit tumor growth. Thus, WIP2W stands out as a potent and selective WT1 inhibitor, and the M-WIP2W nanoformulation appears promising for the therapeutic treatment of refractory CML as well as other WT1-overexpressing malignant cancers.
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Food protein-derived peptides have garnered considerable attention due to their potential bioactivities and functional properties. However, the limited activity poses a challenge in effective utilization aspects. To overcome this hurdle, various methods have been explored to enhance the activity of these peptides. This comprehensive review offers an extensive overview of pretreatment, preparation methods, and modification strategies employed to augment the activity of food protein-derived peptides. Additionally, it encompasses a discussion on the current status and future prospects of bioactive peptide applications. The review also addresses the standardization of mass production processes and safety considerations for bioactive peptides while examining the future challenges and opportunities associated with these compounds. This comprehensive review serves as a valuable guide for researchers in the food industry, offering insights and recommendations to optimize the production process of bioactive peptides.
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Alimentos , Peptídeos , Peptídeos/químicaRESUMO
Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to achieve antitumor activity. In this work, Co,N-doped carbon dots (CoNCDs) were used as a model nanozyme to evaluate the properties of the anti-tumor mechanism, and effective inhibition of S180 tumor was achieved. Based on CoNCDs' good biocompatibility and therapeutic effect on the tumor, we then introduced the cGAS-STING agonist, and the combination of the CoNCDs and STING agonist significantly inhibited tumor growth, and no significant systemic toxicity was observed. The combined system achieved the enhanced tumor synergistic immunotherapy through TME reprogramming via the peroxidase-like activity of the CoNCDs and cGAS-STING signaling pathway agonist synergistically. Our work provides not only a new effective way to reprogram TME in vivo, but also a promising synergic antitumor therapy strategy.
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Neoplasias , Microambiente Tumoral , Transdução de Sinais , Sistemas do Segundo Mensageiro , Imunoterapia , Carbono , Nucleotidiltransferases , Neoplasias/terapiaRESUMO
Polysaccharide-based nanoparticles formed by the polyelectrolyte complexation between chitosan (CS) and flaxseed gum (FG) was developed in this work, and it was further used as a carrier for bighead carp peptide (BCP) delivery. The CS molecular weight (MW) of 50 kDa and CS/FG mass ratio of 1:2 at pH 3.5 were optimal conditions for the NP preparation, with the minimum particle size (â¼155.1 nm) and the maximum BCP encapsulation efficiency (60.3 %). The BCP-loaded CS/FG NPs exhibited the smallest particle size (175.8 nm). Both CS/FG NPs and CS/FG-BCP NPs exhibited roughly uniform spherical shape. FT-IR spectra confirmed the existence of hydrogen bonds and electrostatic interactions in the nanoparticles. The BCP-loaded NPs displayed a higher thermal stability than BCP. Moreover, the release of BCP was controllable and dose-dependent, following a first-order kinetics model. These findings suggested that our CS/FG NPs are a promising carrier for bioactive peptide delivery.
Assuntos
Carpas , Quitosana , Linho , Nanopartículas , Animais , Portadores de Fármacos/química , Polieletrólitos , Quitosana/química , Espectroscopia de Infravermelho com Transformada de Fourier , Nanopartículas/química , Polissacarídeos , Peptídeos/química , Tamanho da PartículaRESUMO
Scope: This study aimed to evaluate the effects of JK5G postbiotics to regulate imbalanced gut microbiota and its impacts on the efficacy and incidence rate of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Methods: This randomized, double-blind, placebo-controlled trial was conducted in China and included non-squamous or squamous NSCLC patients without EGFR, ROS1, and ALK alteration, treatment-naive, and stage IIIb-IV. Patients were randomly (1:1) divided into two groups to receive four cycles (three weeks for each cycle) of programmed cell death-1 (PD-1) plus chemotherapy plus placebo (control group, n = 30) or to receive PD-1 plus chemotherapy plus JK5G postbiotics (JK5G group, n = 30). The primary endpoint was objective response rate. The secondary endpoints were quality of life (QoL), adverse effects, and the 16S DNA sequencing of gut microbiota, blood inflammatory cytokines, and lymphocyte subsets. This study was registered at www.chictr.org.cn (ChiCTR2200064690). Results: Sixty patients were enrolled. The objective response rate was 36.67% (11/30) in the control group and 50.00% (15/30) in the JK5G group (p = 0.297). The JK5G group had better QoL and nutritional levels, as well as lower depression symptoms than the control group (all p < 0.05). Moreover, the JK5G group had a lower incidence of anemia (63.33% vs. 13.33%, p < 0.001), decreased lymphocyte count (20.00% vs. 0%, p = 0.010), decreased appetite (53.33% vs. 16.67%, p = 0.003), nausea (33.33% vs. 6.67%, p = 0.010), and asthenia (30.00% vs. 6.67%, p = 0.017) than the control group. Moreover, JK5G attenuated gut microbiota imbalance, accompanied by increased Faecalibacterium, Ruminococcaceae, and fecal butyrate concentration, and diminished Escherichia-Shigella. Furthermore, JK5G administration significantly decreased the levels of pro-inflammatory markers, including TNF-α, IL-2, and C-reactive protein (CRP) (all p < 0.05). Significant increases in CD3+CD4+ T cells and CD4/CD8 ratio were observed in the peripheral blood of JK5G group patients (all p < 0.05). The enterotype data showed that patients were clustered into Blautia (E1) and Escherichia-Shigella (E2) enterotypes, and JK5G postbiotics intervention might be related to enterotype modulations. Conclusion: Our current findings indicated that JK5G postbiotics might attenuate irAEs, and enhance the QoL and nutrition levels of advanced NSCLC patients who received ICIs. JK5G postbiotics could also improve the gut microbiota structures and ameliorate the tumor microenvironment and inflammation. Clinical trial registration: www.chictr.org.cn, identifier ChiCTR2200064690.