RESUMEN
To date, most efforts to decolonise curricula have focussed on the arts and humanities, with many believing that science subjects are objective, unbiased, and unaffected by colonial legacies. However, science is shaped by both contemporary and historical culture. Science has been used to support imperialism, to extract and exploit knowledge and natural resources, and to justify racist and ableist ideologies. Colonial legacies continue to affect scientific knowledge generation and shape contemporary research priorities. In the biomedical sciences, research biases can feed into wider health inequalities. Reflection of these biases in our taught curricula risks perpetuating long-standing inequities to future generations of scientists. We examined attitudes and understanding towards decolonising and diversifying the curriculum among students and teaching staff in the biomedical sciences at the University of Bristol, UK, to discover whether our current teaching practice is perceived as inclusive. We used a mixed methods study including surveys of staff (N = 71) and students (N = 121) and focus groups. Quantitative data showed that staff and students think decolonising the curriculum is important, but this is more important to female respondents (P < 0.001). Students are less aware than staff of current efforts to decolonise the curriculum, while students from minority ethnic groups feel less represented by the curriculum than white students. Thematic analysis of qualitative data revealed three themes that are important for a decolonised curriculum in our context: rediscovery, representation and readiness. We propose that this '3Rs framework' could guide future efforts to decolonise and diversify the curriculum in the biomedical sciences and beyond.
RESUMEN
Background: Effective prevention is key to addressing the increasing prevalence and mortality of Alzheimer's disease. Assessing the causal relationship between modifiable entertainment activity factors and the risk of Alzheimer's disease is important for developing public health measures, but establishing causal relationships in epidemiological data may be challenging. Methods: This study using the two-sample Mendelian randomization analysis aimed to investigate the causal effect of entertainment activity factors on the risk of Alzheimer's disease. Summary statistics from publicly available genome-wide association studies were used to analyze 14 modifiable entertainment activity. The inverse variance weighted random effects method as the primary analytical method to estimate causal effects was used. Additionally performed MR-Egger, weighted median and weighted model methods to assess the robustness of the results. The reliability of our findings was validated through systematic sensitivity analyses and tests for heterogeneity. Results: We found significant correlation between time spent using computer (odds ratio 0.998; 95% confidence interval 0.996-0.999; p = 0.013) and Alzheimer's disease, compared to other studied entertainment activities that had no significant causal relationship with Alzheimer's disease. Conclusion: Our findings support the hypothesis that increased computer use may reduce the risk of Alzheimer's disease, providing potential strategic directions for the prevention of neurodegenerative diseases.
RESUMEN
Grade II/III gliomas have a highly heterogeneous clinical course. Identifying prognostic biomarkers in grade II/III gliomas is essential to guide clinical management. We explored epithelial-mesenchymal transition (EMT)-related genes to uncover prognostic features in grade II/III gliomas. Consensus cluster analysis of 200 EMT-related genes classified 512 grade II/III glioma samples into two molecular subtypes, C1 and C2. The C1 subtype had significantly worse overall survival compared to the C2 subtype. Pathway analysis revealed C1 tumors were highly associated with tumor progression pathways and demonstrated higher immune cell infiltration scores. Differential expression analysis identified four genes (ACTN1, AQP1, LAMC3, NRM) that discriminated the two subtypes. Validation in external datasets confirmed that high expression of this four-gene signature predicted poor prognosis in grade II/III gliomas. Cellular experiments showed ACTN1, AQP1 and NRM promoted glioma cell proliferation, migration and invasion. We examined correlations of the signature genes with T cell exhaustion markers and found ACTN1 expression had the strongest association. Immunohistochemistry analysis further demonstrated that ACTN1 protein expression in grade II/III gliomas was negatively correlated with patient overall survival. In summary, our study identified a concise four-gene signature that robustly predicts grade II/III gliomas prognosis across multiple datasets. The signature provides clinical relevance in distinguishing more aggressive grade II/III glioma tumors. Targeting the ACTN1, AQP1 and NRM genes may offer new therapeutic opportunities to improve grade II/III gliomas patient outcomes.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Pronóstico , Neoplasias Encefálicas/patología , Glioma/patología , Transición Epitelial-Mesenquimal/genética , LamininaRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear. METHODS: In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV1 and lung diffusing capacity (DLCOc and DLCOc /alveolar volume [VA]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression. RESULTS: SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV1% predicted (ß=-3.384 [-4.877, -1.892]), DLCOc (ß=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV1%predicted was stronger in COPD (ß=-6.362 [-9.055, -3.670]) than non-COPD (ß=-1.712 [-3.306, -0.118]). Association of SAF with DLCOc and DLCOc/VA were confined to COPD (ß=-0.550 [-0.909, -0.191]; ß=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively). CONCLUSIONS: Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD. TAKE-HOME MESSAGE: Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.
Asunto(s)
Asma , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Fumar/efectos adversos , Fumar/epidemiología , Fumar Tabaco , Piel , Productos Finales de Glicación AvanzadaRESUMEN
Ovarian cancer is the tumor with the highest mortality among gynecological malignancies. Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages (TAMs) in the microenvironment. Colony-stimulating factor 1 (CSF-1) receptor (CSF-1R) plays a key role in regulating the number and differentiation of macrophages in certain solid tumors. There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tumor microenvironment. Here, we explored the antitumor efficacy and possible mechanisms of the CSF - 1R inhibitor pexidartinib (PLX3397) when combined with the first-line chemotherapeutic agent paclitaxel in the treatment of ovarian cancer. We found that CSF-1R is highly expressed in ovarian cancer cells and correlates with poor prognosis. Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo. Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.
RESUMEN
Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01-1.46]) and Alzheimer's disease (1.19 [0.97-1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 [0.98-1.82]) and in participants with diabetes (1.35 [0.94-1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus , Humanos , Femenino , Anciano , Masculino , Productos Finales de Glicación Avanzada , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Piel/diagnóstico por imagenRESUMEN
BACKGROUND: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. METHODS: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. RESULTS: 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. CONCLUSIONS: Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. TRIAL REGISTRATION: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl ) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/ ) under shared catalogue number NTR6831.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Diabetes Mellitus , Hipertensión , Placa Aterosclerótica , Insuficiencia Renal Crónica , Anciano , Femenino , Humanos , Masculino , Aterosclerosis/complicaciones , Enfermedades Cardiovasculares/diagnóstico por imagen , Enfermedades Cardiovasculares/epidemiología , Grosor Intima-Media Carotídeo , Estudios Transversales , Productos Finales de Glicación Avanzada , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/complicaciones , Placa Aterosclerótica/complicaciones , Análisis de la Onda del Pulso , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/complicaciones , Factores de Riesgo , PielRESUMEN
Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.
Asunto(s)
Trampas Extracelulares , Microbioma Gastrointestinal , Pancreatitis , Ratones , Animales , Humanos , Trampas Extracelulares/metabolismo , Interleucina-17/metabolismo , Microbioma Gastrointestinal/fisiología , Pancreatitis/metabolismo , Taurina/metabolismoRESUMEN
Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8+ T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
Asunto(s)
MicroARNs , Factores de Transcripción , Animales , Ratones , Antígenos/metabolismo , Linfocitos T CD8-positivos , Células Dendríticas , Homeostasis , MicroARNs/genética , MicroARNs/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Due to the lack of effective synthetic strategies, the preparation of chemically stable chiral Ag(I) cluster-based materials for assembly remains challenging. Here, we have developed an approach to synthesize three pairs of chiral Ln-Ag(I) cluster-based metal-organic frameworks (MOFs) named l-LnAg5-3D (Ln = Gd for 1-L, Eu for 2-L, and Tb for 3-L) and d-LnAg5-3D (Ln = Gd for 1-D, Eu for 2-D, and Tb for 3-D) by employing a chiral Ag(I) cluster ({Ag5S6}) as the node and Ln3+ ion as the inorganic linker. Structural analysis revealed that the chiral ligands induced chirality through the entire structure, resulting in a chiral helix arrangement of the C3-symmetric chiral {Ag5S6} nodes and Ln3+ ions. These compounds showed high solvent stability in various polar organic solvents. The solid-state circular dichroism (CD) spectra of compounds l-LnAg5-3D and d-LnAg5-3D exhibited obvious mirror symmetrical peaks. The emission spectra in the solid state revealed that compound 1-L only exhibited the emission peak of {Ag5S6}, while compounds 2-L and 3-L exhibited overlapping peaks of Ln3+ and {Ag5S6} at different excitation wavelengths. This demonstrates the tunable photoluminescence from {Ag5S6} to Ln3+ by introducing different Ln3+ ions and manipulating the excitation wavelengths. The study underscores the enhanced stability of Ag(I) cluster-based MOFs achieved through the incorporation of Ln3+ ions and establishes chiral Ln-Ag(I) cluster-based MOFs as promising candidates for advanced materials with tunable photoluminescence.
RESUMEN
The tumor-associated macrophage (TAM) is the most abundant group of immune cells in the tumor microenvironment (TME), which plays a critical role in the regulation of tumor progression and treatment resistance. Based on different polarization status, TAMs may also induce antitumor immune responses or immunosuppression. The present study identified JMJD6 (Jumonji domain-containing 6) as a novel modulator of TAM activation, the upregulation of which was associated with the immunosuppressive activities of TAMs. JMJD6 deficiency attenuated the growth of both Lewis lung carcinoma (LLC) tumors and B16F10 melanomas by reversing M2-like activation of macrophages, and sensitized tumors to immune checkpoint blockades (ICBs). Moreover, the JMJD6-induced inhibition of M2 polarization was potentially mediated by the STAT3/IL-10 signaling. These findings highlight the regulatory activities of JMJD6 in TAM polarization, and the therapeutic potential of JMJD6/STAT3/IL-10 axis blockades to enhance the efficacy of ICBs in cancer treatment.
Asunto(s)
Histona Demetilasas con Dominio de Jumonji , Neoplasias , Macrófagos Asociados a Tumores , Humanos , Línea Celular Tumoral , Interleucina-10/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Macrófagos/patología , Neoplasias/patología , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Microambiente Tumoral , Polaridad CelularRESUMEN
The rapid growth of international student mobility has attracted much research on the many benefits it offers to students, higher education institutions, and societies in general. However, studies on the costs and potential tribulations caused by mobility are comparatively rare, despite increasing evidence of such costs inherent in the marketization of higher education. Furthermore, the few existing studies are predominantly framed in terms of consumerism and the commodification of education, but they give less attention to mobility in the context of wider social issues. The climate crisis is foremost among such social impacts, with the extensive air travel inherent in global mobility patterns causing significant damage, combined with curricula, pedagogies, and institutional strategy that are either ambivalent or contradictory on the climate crisis. This paper examines international student mobility in European higher education to better understand how the environmental costs of higher education can be conceptualized in policy and practice. It contrasts policies and practices that promote international student mobility in Europe-in which mobility has aspects of what are commonly referred to as "public goods"-with initiatives that promote mobility to Europe, which illustrate a historic and ongoing entanglement between European colonialism, higher education, and climate change. It concludes with reflections on possibilities for greater sustainability in international student mobility in Europe.
RESUMEN
In this paper, the relative humidity sensor properties of graphene oxide (GO) and graphene oxide/multiwalled nanotubes (GO/MWNTs) composites have been investigated. Composite sensors were fabricated by direct laser scribing and characterized using UV-vis-NIR, Raman, Fourier transform infrared, and X-ray photoemission spectroscopies, electron scanning microscopy coupled with energy-dispersive X-ray analysis, and impedance spectroscopy (IS). These methods confirm the composite homogeneity and laser reduction of GO/MWNT with dominant GO characteristics, while ISresults analysis reveals the circuit model for rGO-GO-rGO structure and the effect of MWNT on the sensor properties. Although direct laser scribing of GO-based humidity sensor shows an outstanding response (|ΔZ|/|Z| up to 638,800%), a lack of stability and repeatability has been observed. GO/MWNT-based humidity sensors are more conductive than GO sensors and relatively less sensitive (|ΔZ|/|Z| = 163,000%). However, they are more stable in harsh humid conditions, repeatable, and reproducible even after several years of shelf-life. In addition, they have fast response/recovery times of 10.7 s and 9.3 s and an ultra-fast response time of 61 ms when abrupt humidification/dehumidification is applied by respiration. All carbon-based sensors' overall properties confirm the advantage of introducing the GO/MWNT hybrid and laser direct writing to produce stable structures and sensors.
RESUMEN
BACKGROUND: Mitochondrial transcription factor A (TFAM) is a transcription factor that maintains mitochondrial DNA (mtDNA) stabilization and initiates mtDNA replication. However, little is known about the immune regulation function and TFAM expression in immune cells in the tumors. METHODS: Mouse tumor models were applied to analyze the effect of TFAM deficiency in myeloid cell lineage on tumor progression and tumor microenvironment (TME) modification. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were used in the investigation of the altered function and the activated pathway. OVA was used as the model antigen to validate the activation of immune responses in vivo. STING inhibitors were used to confirm the STING activation provoked by Tfam deficient in DCs. RESULTS: The deletion of TFAM in DCs led to mitochondrial dysfunction and mtDNA cytosolic leakage resulting in the cGAS-STING pathway activation in DCs, which contributed to the enhanced antigen presentation. The deletion of TFAM in DCs has interestingly reversed the immune suppressive TME and inhibited tumor growth and metastasis in tumor models. CONCLUSIONS: We have revealed that TFAM knockout in DCs ameliorated immune-suppressive microenvironment in tumors through STING pathway. Our work suggests that specific TFAM knockout in DCs might be a compelling strategy for designing novel immunotherapy methods in the future.
Asunto(s)
Proteínas de Unión al ADN , Células Dendríticas , Proteínas del Grupo de Alta Movilidad , Mitocondrias , Neoplasias , Animales , Ratones , Presentación de Antígeno , Modelos Animales de Enfermedad , ADN Mitocondrial , Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Mitocondrias/patología , Neoplasias/patologíaRESUMEN
Chronic pancreatitis (CP) is characterized by chronic progressive pancreatic inflammation, which leads to the permanent damage of exocrine and endocrine cells. CP causes irreversible morphological and functional changes, and the clinical manifestations includes abdomen pain, steatorrhea and diabetes. CP induces changes in the composition of gut microbiota that could be used as potential biomarkers for pancreatic fibrosis evaluation. Gut microbiota has emerged as key regulator of immunomodulation and gut microbiota-induced immune activation has not been explored in CP. In current study, we profiled gut microbial signatures in mouse CP model, and found that higher proportion of Streptomyces, Turicibacter, Methylobacterium, Enterococcus and Candidatus_Paenicardiniummore were positively associated with the occurrence of pancreatic fibrosis. We then identified increased CD3+T cells and macrophage infiltration in mouse and human CP tissues by transcriptome sequencing data from GEO database. Subsequently, we demonstrated that fecal microbiota transplantation (FMT) from CP mouse (FMT-CP) exacerbated pancreatic fibrosis by increasing CD4+T cells and macrophage infiltration compared to fecal samples obtained from healthy mouse donor (FMT-HC). Our study describes the link between gut microbiota dysbiosis and immune activation in pancreatic fibrotic progression, and highlights the potential therapeutic roles of FMT and CP treatment.
Asunto(s)
Microbioma Gastrointestinal , Pancreatitis Crónica , Humanos , Ratones , Animales , Microbioma Gastrointestinal/fisiología , Pancreatitis Crónica/microbiología , Heces/microbiología , Trasplante de Microbiota Fecal , Modelos Animales de Enfermedad , FibrosisRESUMEN
Different environmental parameters, such as temperature and humidity, aggravate food spoilage, and different volatile organic compounds (VOCs) are released based on the extent of spoilage. In addition, a lack of efficient monitoring of the dosage of pesticides leads to crop failure. This could lead to the loss of food resources and food production with harmful contaminants and a short lifetime. For this reason, precise monitoring of different environmental parameters and contaminations during food processing and storage is a key factor for maintaining its safety and nutritional value. Thus, developing reliable, efficient, cost-effective sensor devices for these purposes is of utmost importance. This paper shows that Poly-(diallyl-dimethyl ammonium chloride)/reduced Graphene oxide (PDAC/rGO) films produced by a simple Layer-by-Layer deposition can be effectively used to monitor temperature, relative humidity, and the presence of volatile organic compounds as indicators for spoilage odors. At the same time, they show potential for electrochemical detection of organophosphate pesticide dimethoate. By monitoring the resistance/impedance changes during temperature and relative humidity variations or upon the exposure of PDAC/rGO films to methanol, good linear responses were obtained in the temperature range of 10-100 °C, 15-95% relative humidity, and 35 ppm-55 ppm of methanol. Moreover, linearity in the electrochemical detection of dimethoate is shown for the concentrations in the order of 102 µmol dm-3. The analytical response to different external stimuli and analytes depends on the number of layers deposited, affecting sensors' sensitivity, response and recovery time, and long-term stability. The presented results could serve as a starting point for developing advanced multi-modal sensors and sensor arrays with high potential for analytical applications in food safety and quality monitoring.
RESUMEN
BACKGROUND AND PURPOSE: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota-derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. EXPERIMENTAL APPROACH: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. KEY RESULTS: Normobiotic FMT alleviated AP-induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD+ (nicotinamide adenine dinucleotide)-associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP-mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD+ levels. Similarly, overexpression of the NAD+ -dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti-inflammatory activities in AP. Importantly, normobiotic FMT-mediated NMN metabolism induced SIRT3-PRDX5 pathway activation during AP. CONCLUSION AND IMPLICATIONS: Gut microbiota-derived NMN alleviates the severity of AP by activating the SIRT3-PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment.
Asunto(s)
Microbioma Gastrointestinal , Pancreatitis , Sirtuina 3 , Ratones , Ratas , Animales , Pancreatitis/tratamiento farmacológico , Mononucleótido de Nicotinamida/farmacología , Sirtuina 3/metabolismo , NAD/metabolismo , Disbiosis , Ceruletida , Enfermedad Aguda , InflamaciónRESUMEN
Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar cells. Secondary infection and sepsis are independent prognosticators for AP progression and increased mortality. Accumulating anatomical and epidemiological evidence suggests that the dysbiosis of gut microbiota affects the etiology and severity of AP through intestinal barrier disruption, local or systemic inflammatory response, bacterial translocation, and the regulatory role of microbial metabolites in AP patients and animal models. Recent studies discussing the interactions between gut microbiota and the pancreas have opened new scopes for AP, and new therapeutic interventions that target the bacteria community have received substantial attention. This review concentrates on the alterations of gut microbiota and its roles in modulating gut-pancreas axis in AP. The potential therapies of targeting microbes as well as the major challenges of applying those interventions are explored. We expect to understand the roles of microbes in AP diagnosis and treatment.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Pancreatitis , Animales , Humanos , Enfermedad Aguda , PáncreasRESUMEN
BACKGROUND: Metabolic reprogramming provides a new perspective for understanding cancer. The targeting of dysregulated metabolic pathways may help to reprogram the immune status of the tumor microenvironment (TME), thereby increasing the effectiveness of immune checkpoint therapy. Colorectal cancer (CRC), especially colon adenocarcinoma (COAD), is associated with poor patient survival. The aim of the present study was to identify novel pathways involved in the development and prognosis of COAD, and to explore whether these pathways could be used as targets to improve the efficacy of immunotherapy. METHODS: Metabolism-related differentially expressed genes (MRDEGs) between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA) dataset, together with metabolism-related prognostic genes (MRPGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed separately for the MRDEGs and MRPGs. Gene Set Variation Analysis (GSVA) was also performed to explore the role of purine metabolism in COAD tumorigenesis. Consensus clustering of purine metabolism genes with the overall survival (OS) of patients and with anti-tumor immunity was also performed. Pearson correlation analysis was used to identify potential targets that correlated strongly with the expression of immune checkpoints. RESULTS: A 6-gene signature that had independent prognostic significance for COAD was identified, together with a predictive model for risk stratification and prognosis. The most significantly enriched pathway amongst MRDEGs and MRPGs was purine metabolism. Differentially expressed purine metabolism genes could divide patients into two clusters with distinct prognosis and anti-tumor immunity. Further analysis suggested that purine metabolism was involved in anti-tumor immunity. CONCLUSIONS: This study confirmed the importance of metabolism-related pathways and in particular purine metabolism in the tumorigenesis, prognosis and anti-tumor immunity of COAD. We identified a 6-gene prognostic signature comprised of EPHX2, GPX3, PTGDS, NAT2, ACOX1 and CPT2. In addition, four potential immune-metabolic checkpoints (GUCY1A1, GUCY1B1, PDE1A and PDE5A) were identified, which could be used to improve the efficacy of immunotherapy in COAD.