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1.
J Transl Med ; 21(1): 903, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082307

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid progression and poor prognosis. Understanding the genetic mechanisms that affect cancer properties and reprogram tumor immune microenvironment will develop new strategies to maximize the benefits for cancer therapies. METHODS: Gene signatures and biological processes associated with advanced cancer and unfavorable outcome were profiled using bulk RNA sequencing and spatial transcriptome sequencing, Caprin-1 was identified as an oncogenesis to expedite pancreatic cancer growth by activating autophagy. The mechanism of Caprin-1 inducing autophagy activation was further explored in vitro and in vivo. In addition, higher level of Caprin-1 was found to manipulate immune responses and inflammatory-related pathways. The immune profiles associated with increased levels of Caprin-1 were identified in human PDAC samples. The roles of CD4+T cells, CD8+T cells and tumor associated macrophages (TAMs) on clinical outcomes prediction were investigated. RESULTS: Caprin-1 was significantly upregulated in advanced PDAC and correlated with poor prognosis. Caprin-1 interacted with both ULK1 and STK38, and manipulated ULK1 phosphorylation which activated autophagy and exerted pro-tumorigenic phenotypes. Additionally, the infiltrated CD4+T cells and tumor associated macrophages (TAMs) were increased in Caprin-1High tissues. The extensive CD4+T cells determined poor clinical outcome in Caprin-1high patients, arguing that highly expressed Caprin-1 may assist cancer cells to escape from immune surveillance. CONCLUSIONS: Our findings establish causal links between the upregulated expression of Caprin-1 and autophagy activation, which may manipulate immune responses in PDAC development. Our study provides insights into considering Caprin-1 as potential therapeutic target for PDAC treatment.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Autofagia/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Imunidade , Neoplasias Pancreáticas/patologia , Proteínas Serina-Treonina Quinases , Microambiente Tumoral
2.
Nat Commun ; 14(1): 6179, 2023 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-37794047

RESUMO

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.


Assuntos
Armadilhas Extracelulares , Microbioma Gastrointestinal , Pancreatite , Camundongos , Animais , Humanos , Armadilhas Extracelulares/metabolismo , Interleucina-17/metabolismo , Microbioma Gastrointestinal/fisiologia , Pancreatite/metabolismo , Taurina/metabolismo
3.
Microb Pathog ; 177: 106035, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36828341

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Pancreatite Crônica , Humanos , Camundongos , Animais , Microbioma Gastrointestinal/fisiologia , Pancreatite Crônica/microbiologia , Fezes/microbiologia , Transplante de Microbiota Fecal , Modelos Animais de Doenças , Fibrose
4.
Br J Pharmacol ; 180(5): 647-666, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36321732

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Pancreatite , Sirtuína 3 , Camundongos , Ratos , Animais , Pancreatite/tratamento farmacológico , Mononucleotídeo de Nicotinamida/farmacologia , Sirtuína 3/metabolismo , NAD/metabolismo , Disbiose , Ceruletídeo , Doença Aguda , Inflamação
5.
Biomolecules ; 14(1)2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38254659

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Microbiota , Pancreatite , Animais , Humanos , Doença Aguda , Pâncreas
6.
Medicina (Kaunas) ; 58(12)2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36556955

RESUMO

Background and Objectives: Acute pancreatitis (AP) is defined as an acute inflammatory disorder of the pancreas and is a common gastrointestinal disease. Since currently used indicators lack specifics and cannot accurately reflect the phase of disease, better diagnostic approaches need to be explored. Fibrinogen-like protein 1 (FGL-1) is a reactant in acute inflammatory diseases and is increased in the plasma of AP patients. In the current study, we aim to investigate the clinical benefits of FGL-1 in predicting the severity of AP and infected pancreatic necrosis (IPN), which can improve the diagnostic efficiency of AP. Materials and Methods: In this study, 63 patients diagnosed with AP from December 2018 to September 2019 were enrolled. Regarding the severity of AP, patients were separated into severe acute pancreatitis (SAP, n = 12) and No-SAP groups (n = 51). On the basis of infective conditions, patients were divided into IPN (n = 9) and No-IPN (n = 54) groups. The demographic data (sex and age) and blood parameters (WBC, HCT, glucose, calcium, FIB, APTT, PCT, CRP, and FGL-1) were retrospectively analyzed. Results: The plasma FGL-1 levels were increased in both SAP (p < 0.01) and IPN (p < 0.05) subgroups compared to the healthy control group. Multivariate analysis showed that elevated plasma FGL-1 (p < 0.01) and PCT levels (p < 0.05) within 72 h after the onset of AP were positively correlated with the severity of AP, while increased plasma FGL-1 (p < 0.01) and CRP (p < 0.05) levels were positively correlated with the occurrence of IPN. The combination of FGL-1 and PCT showed superiority to both individual markers in SAP prediction. However, the combination of FGL-1 and CRP showed no diagnostic advantage over CRP in IPN prediction. Conclusions: Plasma FGL-1 within 72 h after the onset could be used for the stratification of AP and its infectious complications. The combination of PCT and FGL-1 presents an enormous advantage for the early identification of SAP.


Assuntos
Pancreatite Necrosante Aguda , Humanos , Pancreatite Necrosante Aguda/diagnóstico , Pancreatite Necrosante Aguda/epidemiologia , Estudos Retrospectivos , Doença Aguda , Incidência , Biomarcadores , Índice de Gravidade de Doença , Fibrinogênio
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