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Unraveling the complexities of T cell aging is essential for developing targeted interventions to enhance immune function in the elderly. This article for the Highlights of 2023 Series integrates recent findings published in 2023, offering a panoramic view of the current understanding of T cell aging and its implications.
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Senescência Celular , Linfócitos T , Humanos , Linfócitos T/imunologia , Senescência Celular/imunologia , Animais , Envelhecimento/imunologia , Senescência de Células TRESUMO
BACKGROUND: Cancer-related fatigue (CRF) is considered one of the most prevalent and distressing symptoms among cancer patients and may vary among patients with different cancer types. However, few studies have explored the influence of physical and psychological symptoms on CRF among esophageal cancer (EC) patients without esophagectomy. Therefore, this study aimed to examine the effects of physical and psychological symptoms on CRF among EC patients without esophagectomy. METHODS: In the present study, a cross-sectional study was conducted from February 2021 to March 2022 in Liaoning Province, China. Among the 112 included participants, 97 completed our investigation. The questionnaires used consisted of the Brief Fatigue Inventory (BFI), the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), and demographic and clinical information. Multivariate linear regression was conducted to test the relationships between physical and psychological symptoms and CRF. RESULTS: Of the 97 EC patients, 60.8% reported CRF (BFI ≥ 4). The mean age of the participants was 64.92 years (SD = 8.67). According to the regression model, all the variables explained 74.5% of the variance in CRF. Regression analysis indicated that physical symptoms, including constipation, diarrhoea, and difficulty swallowing, contributed to CRF. On the other hand, depressive symptoms increased the level of CRF among EC patients without esophagectomy. CONCLUSIONS: Given the high prevalence of CRF among EC patients without esophagectomy, it is urgent to emphasize the importance of fatigue management interventions based on physical and psychological symptoms to alleviate CRF in EC patients.
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Neoplasias Esofágicas , Neoplasias , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/epidemiologia , Inquéritos e Questionários , Análise de Regressão , Fadiga/epidemiologia , Fadiga/etiologia , Fadiga/diagnóstico , Qualidade de VidaRESUMO
Objective: This study aims to explore the effect of YiQi GuBen capsule on improving mitochondrial dysfunction in an animal model of asthma.Methods: The mice (n = 8) were divided into four groups including control (NC), ovalbumin (OVA), dexamethasone (OVA + DEX), and YiQi GuBen (OVA + YQGB) groups. Firstly, we established an OVA-induced mouse asthma model except for the NC group, which then were treated with dexamethasone and YiQi GuBen capsule. Subsequently, HE staining and Masson staining were used for pathological analysis of mice lung tissues. Next, we used transmission electron microscopy (TEM) to observe the effect of the Yiqi Guben capsule on the ultrastructure of mitochondria. Flow cytometry was used to analyze the ROS level, membrane potential, and the number of mitochondria in lung tissue. Moreover, we analyzed the copy number of mitochondrial DNA (mtDNA) and the expression levels of activator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM).Results: The results of the pathological analysis showed that after treatment with the YiQi GuBen capsule, the lung tissue damage was significantly reduced. In addition, we observed that the ultrastructural damage of mitochondria was improved. Flow cytometry proved that after treatment with the YiQi GuBen capsule, the level of ROS in the mitochondria was effectively reduced, while the mitochondrial membrane potential decreased and the number increased significantly. Moreover, we found that the copy number of mtDNA was significantly increased and the expression levels of PGC-1α and TFAM were significantly upgraded.Conclusion: This study suggests YiQi GuBen capsule can effectively improve mitochondrial dysfunction in the OVA-induced mouse model.
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Asma , DNA Mitocondrial , Medicamentos de Ervas Chinesas , Pulmão , Mitocôndrias , Ovalbumina , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Oxigênio , Animais , Asma/tratamento farmacológico , Asma/patologia , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Espécies Reativas de Oxigênio/metabolismo , DNA Mitocondrial/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Feminino , Dexametasona/farmacologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Cápsulas , Proteínas de Grupo de Alta MobilidadeRESUMO
Hepatocellular carcinoma (HCC) is a serious neoplastic disease with increasing incidence and mortality, accounting for 90% of all liver cancers. Hepatitis viruses are the major causative agents in the development of HCC. Hepatitis A virus (HAV) primarily causes acute infections, which is associated with HCC to a certain extent, as shown by clinicopathological studies. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections lead to persistent liver inflammation and cirrhosis, disrupt multiple pathways associated with cellular apoptosis and proliferation, and are the most common viral precursors of HCC. Mutations in the HBV X protein (HBx) gene are closely associated with the incidence of HCC, while the expression of HCV core proteins contributes to hepatocellular lipid accumulation, thereby promoting tumorigenesis. In the clinical setting, hepatitis D virus (HDV) frequently co-infects with HBV, increasing the risk of chronic hepatitis. Hepatitis E virus (HEV) usually causes acute infections. However, chronic infections of HEV have been increasing recently, particularly in immuno-compromised patients and organ transplant recipients, which may increase the risk of progression to cirrhosis and the occurrence of HCC. Early detection, effective intervention and vaccination against these viruses may significantly reduce the incidence of liver cancer, while mechanistic insights into the interplay between hepatitis viruses and HCC may facilitate the development of more effective intervention strategies. This article provides a comprehensive overview of hepatitis viruses and reviews recent advances in research on aberrant hepatic immune responses and the pathogenesis of HCC due to viral infection.
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Carcinoma Hepatocelular , Hepatite B Crônica , Hepatite B , Hepatite C , Hepatite Viral Humana , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Hepatite B Crônica/complicações , Hepatite B/complicações , Hepatite Viral Humana/complicações , Hepatite C/complicações , Cirrose Hepática/complicaçõesRESUMO
Introduction: The present study aimed to investigate the effect of resilience on sleep quality and explore the role of social support between resilience and sleep quality in cancer patients. Methods: A multicenter and cross-sectional study was conducted in China from May to November 2021. A total of 202 cancer patients were recruited to complete the questionnaires composed of demographic information, Pittsburg Sleep Quality Index (PSQI), Resilience Scale-14 (RS-14), and Multidimensions Scale of Perceived Social Support (MSPSS). The associations between resilience, social support, and sleep quality were explored through hierarchical regression analysis. Results: The prevalence of poor sleep quality was 50% among cancer patients. Resilience, social support, and the interaction between resilience and social support were all found to be significantly associated with sleep quality. Results of simple slope analysis indicated that the association between resilience and sleep quality were gradually decreased with the increasing social support levels (1 SD below the mean, B=-0.225, ß=-0.551, P<0.001), mean social support (B=-0.147, ß=-0.353, P<0.001) and high social support (1 SD above the mean, B=-0.065, ß=-0.156, P<0.001). Additionally, social support mediated the effect of resilience on sleep quality among cancer patients. Discussion: Poor sleep quality has been common in cancer patients. Social support could mediate and alleviate the relationship between resilience and sleep quality among cancer patients. Besides providing sufficient social support, interventions based on resilience should be applied to address sleep problems in cancer patients.
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BACKGROUND: Infant hepatitis syndrome (IHS) is a clinical syndrome in infants less than one year of age with generalized skin jaundice, abnormal liver function, and hepatomegaly due to various etiologies such as infection. AIM: To investigate the effect of IHS patients, after treatment with arsphenamine-based peptides, on patients' liver function damage and immune function. METHODS: Of 110 patients with IHS treated in our hospital from January 2019 to January 2021 were grouped according to the randomized residual grouping method, with 5 cases in each group shed due to transfer, etc. Ultimately, 50 cases remained in each group. The control group was treated with reduced glutathione, and the treatment group was treated with sesquiterpene peptide based on the control group. Observe and compare the differences in indicators after treatment. RESULTS: The comparison of serum total bilirubin, direct bilirubin, and serum alanine transferase after treatment was significantly different and lower in the treatment group than in the control group (P < 0.05). The comparison of CD4+, CD3+, CD4+/CD8+ after treatment was significantly different and higher in the treatment group than in the control group, and the comparison was statistically significant (P < 0.05). The complication of the two groups showed that the rash, cough and sputum, elevated platelets, and gastrointestinal reactions in the treatment group were significantly lower than those in the control group, and the differences were statistically significant by test (P < 0.05). CONCLUSION: The comparative study of IHS treated with arsphenamine combined with reduced glutathione is more effective.
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Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the JC1 staining images in Fig. 2C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Molecular Medicine Reports, or were under consideration for publication at around the same time (a small number of which have been retracted). In addition, the Snail western blot data in Fig. 3E bore a close similarity to certain of the Mfn2 data shown in Fig. 4A. In view of the fact that certain of the contentious data had already apparently been published previously, and owing to a lack of confidence in the presentation of certain of the data in this paper, the Editor of Molecular Medicine Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 398404, 2020; DOI: 10.3892/mmr.2020.11098].
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The increase in the styrene content in styrene-butadiene rubber (SBR) can improve the abrasion performance and cutting resistance of rubber, which has received attention in the tire industry. The fatigue performance is the main evaluation index of rubber materials applied to tires. In this study, the effect of the styrene content and its interaction with carbon black (CB) on the dynamic fatigue performance and mechanism of SBR were investigated. The results indicated that the dynamic fatigue life of the rubber composite materials was prolonged with increasing styrene content; furthermore, it showed a trend of increasing and then decreasing with increasing CB content. At a certain CB content, styrene and CB displayed a synergistic effect on improving the dynamic fatigue life of the composite materials. The dynamic fatigue performance of SBR40/CB20 was the best. The expansion of the fatigue cracks followed the secondary cracking mechanism, which consumed a large amount of strain energy and slowed the development of the main crack. However, when the CB content exceeded 40 phr, the mechanism transformed to main crack self-propagation and the fatigue life decreased.
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Conductive hydrogels have shown promising application prospects in the field of flexible sensors, but they often suffer from poor mechanical properties, low sensitivity, and lack of frost resistance. Herein, we report a tough, highly sensitive, and antifreeze strain sensor assembled from a conductive organohydrogel composed of a dual-cross-linked polyacrylamide and poly(vinyl alcohol) (PVA) network, as well as MXene nanosheets as nanofillers and poly(3,4-ethylenedioxythiophene)-doped poly(styrenesulfonate) (PEDOT/PSS) as the main conducting component (PPMP-OH organohydrogel). The tensile strength and toughness of PPMP-OH had been greatly enhanced by MXene nanosheets due to the mechanical reinforcement of MXene nanosheets, as well as various strong noncovalent interactions formed in the organohydrogels. The PPM1P-OH organohydrogels showed a tensile strength of 1.48 MPa at 772% and a toughness of 5.59 MJ/m3. Moreover, the conductivity and strain-sensing performance of PPMP-OH were significantly improved by PEDOT/PSS, which can form hydrogen bonds with PVA and electrostatic interactions with MXene. This was greatly beneficial for constructing a uniformly distributed and stable 3D conductive network and helped to obtain strain-dependent resistance of PPMP-OH. The strain sensors assembled from PPMP1-OH exhibited a high sensitivity of 5.16, a wide range of detectable strains up to 500%, and a short response time of 122 ms, which can effectively detect various physiological activities of the human body with high stability. In addition, the corresponding pressure sensor array also showed high sensitivity in identifying pressure magnitude and position.
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Aquaporin Z (AqpZ), a bacterial water channel, forms a tetrameric complex and, like many other membrane proteins, activity is regulated by lipids. Various methods have been developed to facilitate structure determination of membrane proteins, such as the use of antibodies. Here, we graft onto AqpZ the ALFA tag (AqpZ-ALFA), an alpha helical epitope, to make use of the high-affinity anti-ALFA nanobody (nB). Native mass spectrometry reveals the AqpZ-ALFA fusion forms a stable, 1:1 complex with nB. Single-particle cryogenic electron microscopy studies reveal the octameric (AqpZ-ALFA)4(nB)4 complex forms a dimeric assembly and the structure was determined to 1.9 Å resolution. Dimerization of the octamer is mediated through stacking of the symmetrically bound nBs. Tube-like density is also observed, revealing a potential cardiolipin binding site. Grafting of the ALFA tag, or other epitope, along with binding and association of nBs to promote larger complexes will have applications in structural studies and protein engineering.
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Native mass spectrometry (MS) is revealing the role of specific lipids in modulating membrane protein structure and function. Membrane proteins solubilized in detergents are often introduced into the mass spectrometer; however, commonly used detergents for structural studies, such as dodecylmaltoside, tend to generate highly charged ions, leading to protein unfolding, thereby diminishing their utility for characterizing protein-lipid interactions. Thus, there is a critical need to develop approaches to investigate protein-lipid interactions in different detergents. Here, we demonstrate how charge-reducing molecules, such as spermine and trimethylamine-N-oxide, enable characterization of lipid binding to the bacterial water channel (AqpZ) and ammonia channel (AmtB) in complex with regulatory protein GlnK in different detergent environments. We find protein-lipid interactions are not only protein-dependent but can also be influenced by the detergent and type of charge-reducing molecule. AqpZ-lipid interactions are enhanced in LDAO (n-dodecyl-N,N-dimethylamine-N-oxide), whereas the interaction of AmtB-GlnK with lipids is comparable among different detergents. A fluorescent lipid binding assay also shows detergent dependence for AqpZ-lipid interactions, consistent with results from native MS. Taken together, native MS will play a pivotal role in establishing optimal experimental parameters that will be invaluable for various applications, such as drug discovery, as well as biochemical and structural investigations.
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Chronic obstructive pulmonary disease (COPD) is a significant public health issue characterized by progressive and irreversible airflow limitation. The aim of this meta-analysis was to determine the association between changes in serum galectin-3 levels and COPD and to assess the relationship between serum galectin-3 levels and acute exacerbations of COPD (AECOPD). Relevant observational studies were retrieved from electronic databases, including PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI). A random-effects model was used to combine the data, incorporating the influence of between-study heterogeneity. Twelve case-control studies were included. The pooled results showed a significantly higher serum level of galectin-3 in patients with COPD compared to controls (standardized mean difference [SMD] 0.60; 95% confidence interval [CI] 0.40 - 0.80; P < 0.001; I2 = 68%). Further meta-analysis suggested higher levels of serum galectin-3 in patients with AECOPD compared to those with stable COPD (SMD 0.33; 95% CI 0.20 - 0.46; P < 0.001; I2 = 0%). Subgroup analyses according to the mean age of the participants, the proportion of males, and study quality scores did not significantly change the results (P for subgroup differences all > 0.05). In conclusion, patients with COPD were found to have higher serum levels of galectin-3, with levels further elevated in patients with AECOPD compared to those with stable COPD.
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BACKGROUND: Tic disorder is a common neurodevelopmental disorder in childhood, characterized primarily by motor or vocal tics. However, there is no systematic evaluation of pediatric massage therapy for children with Tic disorder. This study aims to evaluate the effectiveness and safety of massage therapy for children with tic disorder through a comprehensive meta-analysis and systematic review. METHODS: We systematically searched relevant randomized controlled trials from various databases such as CBM, CNKI, VIP, Wanfang database, PubMed, Embase, Web of Science, Cochrane Library, and SINOMED, published up to October 2023. To collect randomized controlled trials on pediatric massage therapy or in combination with other therapies for the treatment of tic disorders in children. The risk of bias in the included articles was assessed using the Cochrane guideline. Meta-analyses were performed using Review Manager 5.4, and publication bias was evaluated by using Begg test and Egger test in Stata SE software. RESULTS: This meta-analysis included 19 randomized controlled trials with 1423 patients. Pediatric massage therapy alone or in combination with conventional medication demonstrated a significant increase in clinical effectiveness rates [risk ratiosâ =â 1.15, 95% confidence interval [CI] (1.10, 1.20), Zâ =â 6.54, Pâ <â .001], and reduced Yale Global Tie Severity Scale scores [standardized mean differenceâ =â -0.85, 95% CI (-1.50, -0.19), Zâ =â 2.54, Pâ =â .01] and traditional Chinese medicine syndrome scores [standardized mean differenceâ =â -1.35, 95%CI (-2.08, -0.63), Zâ =â 3.66, Pâ =â .0002]. In terms of adverse reactions, there was no statistical difference between the experimental and control groups [risk ratiosâ =â 0.26, 95% CI (0.14, 0.49), Zâ =â 4.25, Pâ <â .001]. The Begg test and Egger test results indicated no publication bias. CONCLUSION: Evidence suggests that pediatric massage therapy is effective in improving tic disorders in children.
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Massagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos de Tique , Humanos , Massagem/métodos , Transtornos de Tique/terapia , Criança , Resultado do Tratamento , Pré-EscolarRESUMO
Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO3-) exchange for chloride (Cl-) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I-) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl-, I-, HCO3- or in the apo-state. The structures reveal two anion-binding sites in each protomer, and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate Transporter and Anti-Sigma factor antagonist (STAS) and transmembrane domains, and mutational studies suggest a regulatory role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal directions for understanding the mechanisms of anion selectivity and exchange and their regulations by the STAS domain. This work also establishes a foundation for analyzing the pathophysiology of mutations associated with Pendred syndrome.
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Perda Auditiva Neurossensorial , Humanos , Bicarbonatos , Cloretos , Microscopia Crioeletrônica , Halogênios , Suínos , AnimaisRESUMO
The widespread use of emerging refractory organic contaminants poses a significant threat to human health, prompting the need for a cost-effective and efficient removal strategy. While the iron ions/PMS system effectively removes organic pollutants, slow Fe3+ to Fe2+ transformation hampers its efficiency, and the homogeneous distribution of iron ions complicates separation, resulting in secondary sludge pollution. Herein, we developed a novel submicron Fe-MoS2 (S-Fe-MoS2) catalyst with abundant surface cationic groups and sulfur vacancy through a cationic polyacrylamide aerogels (CPAMA) confined hydrothermal synthesis strategy. These features promote active site exposure, enhance reactant adsorption, and accelerate electron transfer between Mo and Fe sites, improving catalytic kinetics and promoting Fe3+/Fe2+ cycle for PMS activation. As a result, the S-Fe-MoS2/PMS system exhibited a high catalytic rate constant (kobs) of 0.32â min-1, in the degradation of 4-chlorophenol (4-CP), 1.5 times higher than that of the conventional Fe-MoS2/PMS system. It also achieved 82.9% total organic carbon (TOC) degradation within 60â min. Additionally, it possessed similar degradation performance for various organic pollutants, along with remarkable reusability (four cycles) and broad pH adaptability (2-8), indicating significant potential for widespread application. This study provided a new way for developing advanced heterogeneous catalysts with high efficiency for water treatment.
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Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.
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Homovanillic acid (HVA) is a major dopamine metabolite, and blood HVA is considered as central nervous system (CNS) dopamine biomarker, which reflects the progression of dopamine-associated CNS diseases and the behavioral response to therapeutic drugs. However, facing blood various active substances interference, particularly structurally similar catecholamines and their metabolites, real-time and accurate monitoring of blood HVA remains a challenge. Herein, a highly selective implantable electrochemical fiber sensor based on a molecularly imprinted polymer is reported to accurately monitor HVA in vivo. The sensor exhibits high selectivity, with a response intensity to HVA 12.6 times greater than that of catecholamines and their metabolites, achieving 97.8% accuracy in vivo. The sensor injected into the rat caudal vein tracked the real-time changes of blood HVA, which paralleled the brain dopamine fluctuations and indicated the behavioral response to dopamine increase. This study provides a universal design strategy for improving the selectivity of implantable electrochemical sensors.
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Catecolaminas , Dopamina , Ratos , Animais , Ácido Homovanílico/metabolismo , Encéfalo/metabolismoRESUMO
BACKGROUND: The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application. METHODS: Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9+CD14+ monocytes play a role in ICB resistance. RESULTS: Our study demonstrates a notable enrichment of S100A9+CD14+ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma. CONCLUSIONS: Our study underscores the significance of S100A9+CD14+ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Monócitos/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T/metabolismo , Imunoterapia , Microambiente Tumoral , Calgranulina B/metabolismoRESUMO
Regulatory T (Treg) cells play a critical regulatory role in the immune system by suppressing excessive immune responses and maintaining immune balance. The effective migration of Treg cells is crucial for controlling the development and progression of inflammatory diseases. However, the mechanisms responsible for directing Treg cells into the inflammatory tissue remain incompletely elucidated. In this study, we identified BAF60b, a subunit of switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complexes, as a positive regulator of Treg cell migration that inhibits the progression of inflammation in experimental autoimmune encephalomyelitis (EAE) and colitis animal models. Mechanistically, transcriptome and genome-wide chromatin-landscaped analyses demonstrated that BAF60b interacts with the transcription factor RUNX1 to promote the expression of CCR9 on Treg cells, which in turn affects their ability to migrate to inflammatory tissues. Our work provides insights into the essential role of BAF60b in regulating Treg cell migration and its impact on inflammatory diseases.
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Movimento Celular , Inflamação , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Camundongos , Inflamação/patologia , Inflamação/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/genética , Humanos , Fatores de Transcrição/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Colite/metabolismo , Colite/patologia , Colite/imunologia , Colite/genéticaRESUMO
BACKGROUND: Extreme heat exposure is a growing health problem, and the effects of heat on the gastrointestinal (GI) tract is unknown. This study aimed to assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. AIM: To assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. METHODS: Patients admitted to the intensive care unit (ICU) due to heatstroke were included from 83 centres. Patient history, laboratory results, and clinically relevant outcomes were recorded at ICU admission and daily until up to day 15, ICU discharge, or death. GI symptoms, including nausea/vomiting, diarrhoea, flatulence, and bloody stools, were recorded. The characteristics of patients with heatstroke concomitant with GI symptoms were described. Multivariable regression analyses were performed to determine significant predictors of GI symptoms. RESULTS: A total of 713 patients were included in the final analysis, of whom 132 (18.5%) patients had at least one GI symptom during their ICU stay, while 26 (3.6%) suffered from more than one symptom. Patients with GI symptoms had a significantly higher ICU stay compared with those without. The mortality of patients who had two or more GI symptoms simultaneously was significantly higher than that in those with one GI symptom. Multivariable logistic regression analysis revealed that older patients with a lower GCS score on admission were more likely to experience GI symptoms. CONCLUSION: The GI manifestations of heatstroke are common and appear to impact clinically relevant hospitalization outcomes.