RESUMEN
Acute pancreatitis (AP) is a sudden-onset disease of the digestive system caused by abnormal activation of pancreatic enzymes. Dual oxidase 2 (DUOX2) has been found to be elevated in the progression of a variety of inflammatory diseases. Therefore, we analyzed the specific roles of DUOX2 in AP development. Blood samples were collected from of AP patients and healthy people, and the caerulein- stimulated human pancreatic duct cells (H6C7) were utilized to establish an AP cell model. Cell growth and apoptosis were measured using an MTT assay and TUNEL staining. Additionally, RT-qPCR and western blot assays were conducted to assess the RNA and protein expressions of the cells. ELISA kits were used to determine TNF-α, IL-6, IL-8, and IL-1ß levels. The interaction between DUOX2 and miR-605-3p was predicted using the Targetscan database and confirmed by dual-luciferase report assay. We found that DUOX2 increased while miR-605-3p decreased in the blood of AP patients and caerulein-stimulated H6C7 cells. DUOX2 was targeted by miR-605-3p. Furthermore, DUOX2 knockdown or miR-605-3p overexpression promoted cell viability, decreased the TNF-α, IL-6, IL-8, and IL-1ß levels, and inhibited apoptosis rate in caerulein-stimulated H6C7 cells. DUOX2 knockdown or miR-605-3p overexpression also increased the Bcl-2 protein levels and down-regulated Bax, cleaved-caspase-1, NLRP3 and p-p65. Interestingly, DUOX2 overexpression reversed the miR-605-3p mimic function in the caerulein-treated H6C7 cells. In conclusion, our research demonstrated that DUOX2 knockdown relieved the injury and inflammation in caerulein-stimulated H6C7 cells.
Asunto(s)
Ceruletida , Oxidasas Duales , MicroARNs , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Pancreatitis , Piroptosis , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Oxidasas Duales/metabolismo , Oxidasas Duales/genética , Pancreatitis/patología , Pancreatitis/metabolismo , Pancreatitis/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , FN-kappa B/metabolismo , Transducción de Señal , Masculino , Línea Celular , Conductos Pancreáticos/patología , Conductos Pancreáticos/metabolismo , Apoptosis , Femenino , Persona de Mediana EdadRESUMEN
Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.
Asunto(s)
Mitocondrias , Mitofagia , Pancreatitis , Humanos , Pancreatitis/metabolismo , Pancreatitis/patología , Animales , Mitocondrias/metabolismo , Enfermedad AgudaRESUMEN
The current research was designed to investigate the impact of whole-process high-quality nursing on acute pancreatitis (AP) patients' quality of life as well as the mechanism of miR-126-5p/HOXC8 axis promoting AP progression. One hundred AP patients admitted to our hospital were chosen and separated into control group (CG, n=50) and study group (SG, n=50). The CG took the routine nursing, while the SG adopted the whole-process high-quality nursing. Besides, cerulein (CE) was treated in AR42J cells to establish an experimental model of AP. The proliferation, apoptosis along with inflammation of CE-treated AR42J cells were assessed. The outcomes manifested that in contrast to the CG, the recovery time of bowel sound, the improvement time of abdominal distension, the improvement time of abdominal pain, the exhaust time and the defecation time in the SG presented shorter, the anxiety and depression scores in the SG presented lower, the WHOQOL-100 scores of patients in the SG presented higher in the fields of physiology, psychology, environment and social relations, the total incidence of complications of the SG presented lower, and the total nursing satisfaction of the SG was better. Besides, miR-126-5p presented upregulation in CE-stimulated AR42J cells, and miR-126-5p inhibition increased the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. Moreover, HOXC8 could be the target mRNA of miR-126-5p, and HOXC8 elevation promoted the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. In addition, rescue assays further validated that HOXC8 silence offset the protective impact of miR-126-5p repression on AP cell damage. In conclusion, our study indicated that whole-process high-quality nursing could promote the quality of life of AP patients, and revealed that miR-126-5p inhibition relieved CE-stimulated AR42J cells injury caused by AP via targeting HOXC8. Our study might offer novel insights for AP treatment and nursing.
Asunto(s)
Apoptosis , Progresión de la Enfermedad , Proteínas de Homeodominio , MicroARNs , Pancreatitis , Calidad de Vida , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Pancreatitis/patología , Pancreatitis/genética , Masculino , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Apoptosis/genética , Femenino , Proliferación Celular , Persona de Mediana Edad , Enfermedad Aguda , Adulto , Ratas , AnimalesRESUMEN
Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa-Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease.
Asunto(s)
Glucuronidasa , Pancreatitis , Animales , Pancreatitis/tratamiento farmacológico , Pancreatitis/patología , Ratones , Glucuronidasa/metabolismo , Glucuronidasa/antagonistas & inhibidores , Trehalosa/farmacología , Trehalosa/uso terapéutico , Ceruletida , Aspirina/farmacología , Aspirina/uso terapéutico , Modelos Animales de Enfermedad , Enfermedad Aguda , Autofagia/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/enzimología , Masculino , Ratones Transgénicos , Lipasa/metabolismo , Lipasa/antagonistas & inhibidores , Amilasas/sangre , Ratones Endogámicos C57BL , SaponinasRESUMEN
Acute pancreatitis (AP) is an inflammatory disease initiated by the death of exocrine acinar cells, but its pathogenesis remains unclear. Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates immunity and the inflammatory response. The protective role of STAT3 is reported in Coxsackievirus B3 (CVB3)-induced cardiac fibrosis, yet the exact role of STAT3 in modulating viral-induced STAT1 activation and type I interferon (IFN)-stimulated gene (ISG) transcription in the pancreas remains unclarified. In this study, we tested whether STAT3 regulated viral-induced STAT1 translocation. We found that CVB3, particularly capsid VP1 protein, markedly upregulated the phosphorylation and nuclear import of STAT3 (p-STAT3) while it significantly impeded the nuclear translocation of p-STAT1 in the pancreases and hearts of mice on day 3 postinfection (p.i.). Immunoblotting and an immunofluorescent assay demonstrated the increased expression and nuclear translocation of p-STAT3 but a blunted p-STAT1 nuclear translocation in CVB3-infected acinar 266-6 cells. STAT3 shRNA knockdown or STAT3 inhibitors reduced viral replication via the rescue of STAT1 nuclear translocation and increasing the ISRE activity and ISG transcription in vitro. The knockdown of STAT1 blocked the antiviral effect of the STAT3 inhibitor. STAT3 inhibits STAT1 activation by virally inducing a potent inhibitor of IFN signaling, the suppressor of cytokine signaling-3 ((SOCS)-3). Sustained pSTAT1 and the elevated expression of ISGs were induced in SOCS3 knockdown cells. The in vivo administration of HJC0152, a pharmaceutical STAT3 inhibitor, mitigated the viral-induced AP and myocarditis pathology via increasing the IFNß as well as ISG expression on day 3 p.i. and reducing the viral load in multi-organs. These findings define STAT3 as a negative regulator of the type I IFN response via impeding the nuclear STAT1 translocation that otherwise triggers ISG induction in infected pancreases and hearts. Our findings identify STAT3 as an antagonizing factor of the IFN-STAT1 signaling pathway and provide a potential therapeutic target for viral-induced AP and myocarditis.
Asunto(s)
Enterovirus Humano B , Miocarditis , Pancreatitis , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Replicación Viral , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Miocarditis/virología , Miocarditis/metabolismo , Miocarditis/patología , Miocarditis/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Animales , Pancreatitis/metabolismo , Pancreatitis/virología , Pancreatitis/patología , Pancreatitis/genética , Enterovirus Humano B/fisiología , Ratones , Humanos , Infecciones por Coxsackievirus/metabolismo , Infecciones por Coxsackievirus/virología , Infecciones por Coxsackievirus/patología , Infecciones por Coxsackievirus/genética , Núcleo Celular/metabolismo , Masculino , Transporte Activo de Núcleo Celular , Regulación de la Expresión Génica , Enfermedad Aguda , Línea Celular , Transducción de SeñalRESUMEN
Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high-fat diet and retrograde administration of sodium taurocholate were employed to establish the HP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator-activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism-related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin-8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α-amylase, total cholesterol, low-density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high-density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP-1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP.
Asunto(s)
Hiperlipidemias , Metabolismo de los Lípidos , Diana Mecanicista del Complejo 2 de la Rapamicina , PPAR alfa , Pancreatitis , Ratas Sprague-Dawley , Animales , PPAR alfa/metabolismo , PPAR alfa/genética , Ratas , Pancreatitis/metabolismo , Pancreatitis/patología , Pancreatitis/inducido químicamente , Pancreatitis/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/genética , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Técnicas de Silenciamiento del GenRESUMEN
Acute pancreatitis, a common exocrine inflammatory disease affecting the pancreas, is characterized by intense abdominal pain and multiple organ dysfunction. However, the alterations in retinal blood vessels among individuals with acute pancreatitis remain poorly understood. This study employed optical coherence tomography angiography (OCTA) to examine the superficial and deep retinal blood vessels in patients with pancreatitis. Sixteen patients diagnosed with pancreatitis (32 eyes) and 16 healthy controls (32 eyes) were recruited from the First Affiliated Hospital of Nanchang University for participation in the study. Various ophthalmic parameters, such as visual acuity, intraocular pressure, and OCTA image for retina consisting of the superficial retinal layer (SRL) and the deep retinal layer (DRL), were recorded for each eye. The study observed the superficial and deep retinal microvascular ring (MIR), macrovascular ring (MAR), and total microvessels (TMI) were observed. Changes in retinal vascular density in the macula through annular partitioning (C1-C6), hemispheric quadrant partitioning (SR, SL, IL, and IR), and early diabetic retinopathy treatment studies (ETDRS) partitioning methods (R, S, L, and I). Correlation analysis was employed to investigate the relationship between retinal capillary density and clinical indicators. Our study revealed that in the superficial retinal layer, the vascular density of TMI, MIR, MAR, SR, IR, S, C2, C3 regions were significantly decreased in patients group compared with the normal group. For the deep retinal layer, the vascular density of MIR, SR, S, C1, C2 regions also reduced in patient group. The ROC analysis demonstrated that OCTA possesses significant diagnostic performance for pancreatitis. In conclusion, patients with pancreatitis may have retinal microvascular dysfunction, and OCTA can be a valuable tool for detecting alterations in ocular microcirculation in pancreatitis patients in clinical practice.
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Pancreatitis , Vasos Retinianos , Tomografía de Coherencia Óptica , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Relevancia Clínica , Microvasos/diagnóstico por imagen , Microvasos/patología , Microvasos/fisiopatología , Pancreatitis/complicaciones , Pancreatitis/patología , Pancreatitis/fisiopatología , Vasos Retinianos/diagnóstico por imagen , Vasos Retinianos/patología , Tomografía de Coherencia Óptica/métodos , Agudeza VisualRESUMEN
OBJECTIVES: This study aimed to evaluate the therapeutic effects of forsythoside A (FA) on brain injury induced by severe acute pancreatitis (SAP) using a murine model. METHODS: Mice were induced with 3.5â¯% sodium taurocholate to model SAP-induced brain injury (SAP-IBI) and were randomly assigned to four distinct treatment regimens: the SAP-IBI model group (SAP-IBI), low-dose FA treatment group (FA L+SI), middle-dose FA treatment group (FA M+SI), and high-dose FA treatment group (FA H+SI). A sham-operation group (SO) served as a negative control. Serum levels of interleukin-1ß (IL-1ß) and IL-18 were quantified via ELISA, and serum amylase levels were assessed using optical turbidimetry. mRNA expression levels of AIM2, ASC, Caspase-1, and GAPDH in hippocampal brain tissue were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Protein levels of NLRP3, GSDMD, IL-1ß, and IL-18 in hippocampal brain tissue were evaluated using Western blotting. Neurological function in surviving mice was assessed through modified neurological severity scores (mNSS). Transmission electron microscopy (TEM) provided ultrastructural analysis of the hippocampus. Additionally, water content and pathological changes in hippocampal brain tissue were examined 24â¯hours post-operation, along with other relevant indicators. RESULTS: At 24â¯hours post-operation, the FA H+SI group exhibited significantly reduced levels of serum amylase, IL-1ß, and IL-18, along with decreased expression of AIM2, ASC, and Caspase-1 mRNA. Furthermore, NLRP3 protein levels, water content, pancreas and hippocampal brain pathological scores, and mNSS were significantly lower compared to the SAP-IBI group (P<0.01). CONCLUSIONS: FA demonstrates protective effects against SAP-IBI in mice, suggesting potential therapeutic benefits.
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Lesiones Encefálicas , Glicósidos , Pancreatitis , Animales , Pancreatitis/patología , Pancreatitis/tratamiento farmacológico , Pancreatitis/inducido químicamente , Masculino , Ratones , Lesiones Encefálicas/prevención & control , Lesiones Encefálicas/etiología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/patología , Lesiones Encefálicas/metabolismo , Glicósidos/farmacología , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Enfermedad Aguda , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Exogenous inhibition of neutrophil extracellular traps (NETs) was believed to alleviate acute pancreatitis (AP). This study aimed to comprehensively explore the key biological behavior of NETs including timing and pathogenesis in AP by integrating of single cell RNA sequencing(scRNA-seq) and bulk RNA-seq. METHODS: Differentially expressed NETs-related genes and the hub genes of NETs were screened by bulk RNA-seq. ScRNA-seq was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in neutrophils. The mouse AP models were build to verify the timing of initiation of NETs and underlying pathogenesis of damage on pancreas acinar cells. RESULTS: Tlr4 and Ccl3 were screened for hub genes by bulk RNA-seq. The trajectory analysis of neutrophils showed that high expression of Ccl3, Cybb and Padi4 can be observed in the middle stage during AP. Macrophages might be essential in the biological behavior of neutrophils and NETs. Through animal models, we presented that extensive NETs structures were formed at mid-stage of inflammation, accompanied by more serious pancreas and lung damage. NETs might promote necroptosis and macrophage infiltration in AP, and the damage on pancreatic injury could be regulated by Tlr4 pathway. Ccl3 was considered to recruit neutrophils and promote NETs formation. CONCLUSION: The findings explored the underlying timing and pathogenesis of NETs in AP for the first time, which provided gene targets for further studies.
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Trampas Extracelulares , Ratones Endogámicos C57BL , Neutrófilos , Pancreatitis , Receptor Toll-Like 4 , Trampas Extracelulares/inmunología , Trampas Extracelulares/metabolismo , Animales , Pancreatitis/inmunología , Pancreatitis/genética , Pancreatitis/patología , Neutrófilos/inmunología , Ratones , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Modelos Animales de Enfermedad , Masculino , Humanos , Páncreas/patología , Páncreas/inmunología , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Macrófagos/inmunologíaRESUMEN
Acute pancreatitis (AP) is an inflammatory disease of the pancreas and the main cause of hospital admissions for gastrointestinal diseases. Here, the work studied the circular RNA DTNB/microRNA-485-5p/MCL1 axis in AP and hoped to unravel the related mechanism. Caerulein exposure replicated an AP model in AR42J cells, and caerulein-mediated expression of circDTNB, miR-485-5p, and MCL1 was recorded. After exposure, cells were intervened with transfection plasmids and tested for LDH release, apoptosis, and inflammation. To determine the interwork of circDTNB, miR-485-5p, and MCL1, prediction results and verification experiments were conducted. Caerulein exposure reduced circDTNB and MCL1, while elevated miR-485-5p levels in AR42J cells. Upregulating circDTNB protected AR42J cells from caerulein-induced LDH cytotoxicity, apoptosis, and inflammation, but circDTNB upregulation-induced protections could be muffled by inhibiting MCL1. On the contrary, downregulating circDTNB further damaged AR42J cells under caerulein exposure, however, this phenomenon could be partially rescued after silencing miR-485-5p. miR-485-5p was mechanistically verified to be a target of circDTNB to mediate MCL1. Overall, the circDTNB/miR-485-5p/MCL1 axis protects inflammatory response and apoptosis in caerulein-exposed AR42J cells, promisingly identifying circDTNB as a novel molecule for AP treatment.
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Apoptosis , Ceruletida , Inflamación , MicroARNs , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , ARN Circular , MicroARNs/genética , MicroARNs/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Animales , Ratas , Inflamación/genética , Pancreatitis/genética , Pancreatitis/metabolismo , Pancreatitis/inducido químicamente , Pancreatitis/patología , Línea CelularRESUMEN
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
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Autofagia , Modelos Animales de Enfermedad , Ferroptosis , Peroxidación de Lípido , Pancreatitis , Ratas Sprague-Dawley , Animales , Pancreatitis/metabolismo , Pancreatitis/patología , Ratas , Masculino , Adenina/análogos & derivados , Adenina/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ácido Taurocólico , Ciclohexilaminas/farmacología , Páncreas/patología , Páncreas/metabolismo , Fenilendiaminas/farmacología , Malondialdehído/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedad Aguda , Glutatión/metabolismo , Hierro/metabolismoRESUMEN
Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.
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Ceruletida , Ratones Endogámicos C57BL , Pancreatitis , Animales , Pancreatitis/prevención & control , Pancreatitis/patología , Masculino , Ratones , Femenino , Modelos Animales de Enfermedad , Índice de Severidad de la Enfermedad , Péptidos/farmacología , Páncreas/patología , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Antiinflamatorios/farmacología , Quimasas/metabolismo , MonoaminooxidasaRESUMEN
OBJECTIVES: We aim to assess the early use of contrast-enhanced computed tomography (CECT) of patients with severe acute pancreatitis (SAP) using the computed tomography severity index (CTSI) in prognosis prediction. The CTSI combines quantification of pancreatic and extrapancreatic inflammation with the extent of pancreatic necrosis. METHODS: Post-hoc retrospective analysis of a large, multicentric database (44 institutions) of SAP patients in Japan. The area under the curve (AUC) of the CTSI for predicting mortality and the odds ratio (OR) of the extent of pancreatic inflammation and necrosis were calculated using multivariable analysis. RESULTS: In total, 1097 patients were included. The AUC of the CTSI for mortality was 0.65 (95 % confidence interval [CI:] [0.59-0.70]; p < 0.001). In multivariable analysis, necrosis 30-50 % and >50 % in low-enhanced pancreatic parenchyma (LEPP) was independently associated with a significant increase in mortality, with OR 2.04 and 95 % CI 1.01-4.12 (P < 0.05) and OR 3.88 and 95 % CI 2.04-7.40 (P < 0.001), respectively. However, the extent of pancreatic inflammation was not associated with mortality, regardless of severity. CONCLUSIONS: The degree of necrosis in LEPP assessed using early CECT of SAP was a better predictor of mortality than the extent of pancreatic inflammation.
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Medios de Contraste , Necrosis , Páncreas , Pancreatitis , Tomografía Computarizada por Rayos X , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pancreatitis/diagnóstico por imagen , Pancreatitis/patología , Pancreatitis/mortalidad , Estudios Retrospectivos , Páncreas/diagnóstico por imagen , Páncreas/patología , Estudios de Cohortes , Pronóstico , Adulto , Índice de Severidad de la Enfermedad , Inflamación/diagnóstico por imagen , Japón/epidemiología , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/mortalidad , Pancreatitis Aguda Necrotizante/patologíaRESUMEN
The serine protease chymotrypsin protects the pancreas against pancreatitis by degrading trypsinogen, the precursor to the digestive protease trypsin. Taking advantage of previously generated mouse models with either the Ctrb1 gene (encoding chymotrypsin B1) or the Ctrl gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel Ctrb1-del × Ctrl-KO strain in the C57BL/6N genetic background, which harbors a naturally inactivated Ctrc gene (encoding chymotrypsin C). The newly created mice are devoid of chymotrypsin, yet the animals develop normally, breed well, and show no spontaneous phenotype, indicating that chymotrypsin is dispensable under laboratory conditions. When given cerulein, the Ctrb1-del × Ctrl-KO strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, Ctrb1-del × Ctrl-KO mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in Ctrb1-del × Ctrl-KO mice was highly similar to that previously observed in Ctrb1-del mice; however, trypsin activation was more robust and pancreatitis severity was increased. Taken together, the results confirm and extend prior observations demonstrating that chymotrypsin safeguards the pancreas against pancreatitis by limiting pathologic trypsin activity. In mice, the CTRB1 isoform, which constitutes about 90% of the total chymotrypsin content, is responsible primarily for the anti-trypsin defenses and protection against pancreatitis; however, the minor isoform CTRL also contributes to an appreciable extent.NEW & NOTEWORTHY Chymotrypsins defend the pancreas against the inflammatory disorder pancreatitis by degrading harmful trypsinogen. This study demonstrates that mice devoid of pancreatic chymotrypsins are phenotypically normal but become sensitized to secretagogue hyperstimulation and exhibit increased intrapancreatic trypsin activation, more severe acute pancreatitis, and rapid progression to chronic pancreatitis. The observations confirm and extend the essential role of chymotrypsins in pancreas health.
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Ceruletida , Quimotripsina , Ratones Endogámicos C57BL , Ratones Noqueados , Pancreatitis , Tripsina , Animales , Quimotripsina/metabolismo , Quimotripsina/genética , Ceruletida/toxicidad , Pancreatitis/inducido químicamente , Pancreatitis/patología , Pancreatitis/metabolismo , Pancreatitis/genética , Ratones , Tripsina/metabolismo , Secretagogos/metabolismo , Páncreas/metabolismo , Páncreas/patología , Modelos Animales de Enfermedad , MasculinoRESUMEN
In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.
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Mastocitos , Neovascularización Patológica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/inmunología , Mastocitos/metabolismo , Mastocitos/inmunología , Microambiente Tumoral/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/metabolismo , Páncreas/patología , Páncreas/inmunología , Páncreas/metabolismo , Animales , Pancreatitis/metabolismo , Pancreatitis/patología , Pancreatitis/inmunología , Factores de Riesgo , Mediadores de Inflamación/metabolismo , Triptasas/metabolismo , Inflamación/metabolismoRESUMEN
OBJECTIVE: It was targeted to assess the efficacy of certolizumab on pancreas and target organs via biochemical parameters and histopathologic scores in experimental acute pancreatitis (AP). MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into the following 5 equal groups: group 1 (sham group), group 2 (AP group), group 3 (AP + low-dose certolizumab group), group 4 (AP + high-dose certolizumab group), and group 5 (placebo group). Rats in all groups were sacrificed 24 hours after the last injection and amylase, tumor necrosis factor α, transforming growth factor ß, interleukin 1ß, malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were studied in blood samples. Histopathological investigation of both the pancreas and target organs (lungs, liver, heart, kidneys) was performed by a pathologist blind to the groups. In silico analysis were also accomplished. RESULTS: The biochemical results in the certolizumab treatment groups were identified to be significantly favorable compared to the AP group (P < 0.001). The difference between the high-dose group (group 4) and low-dose treatment group (group 3) was found to be significant in terms of biochemical parameters and histopathological scores (P < 0.001). In terms of the effect of certolizumab treatment on the target organs (especially on lung tissue), the differences between the low-dose treatment group (group 3) and high-dose treatment group (group 4) with the AP group (group 2) were significant. CONCLUSIONS: Certolizumab has favorable protective effects on pancreas and target organs in AP. It may be a beneficial agent for AP treatment and may prevent target organ damage.
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Amilasas , Pulmón , Páncreas , Pancreatitis , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Animales , Masculino , Pancreatitis/prevención & control , Pancreatitis/inducido químicamente , Pancreatitis/patología , Pancreatitis/tratamiento farmacológico , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/metabolismo , Amilasas/sangre , Enfermedad Aguda , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Certolizumab Pegol/farmacología , Malondialdehído/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa/metabolismo , Miocardio/patología , Miocardio/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Ratas , Modelos Animales de Enfermedad , Estrés Oxidativo/efectos de los fármacosRESUMEN
Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin's ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca2+ chelator BAPTA-AM with a high loading content (â¼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs' skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.
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Pancreatitis , Tripsina , Animales , Pancreatitis/tratamiento farmacológico , Pancreatitis/patología , Pancreatitis/metabolismo , Tripsina/metabolismo , Tripsina/química , Ratones , Porosidad , Nanomedicina , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Nanopartículas/química , Dióxido de Silicio/química , Compuestos de Organosilicio/química , Compuestos de Organosilicio/farmacología , Masculino , Humanos , Células Acinares/efectos de los fármacos , Células Acinares/metabolismo , Células Acinares/patología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Severe acute pancreatitis (SAP) is a potentially lethal inflammatory pancreatitis condition that is usually linked to multiple organ failure. When it comes to SAP, the lung is the main organ that is frequently involved. Many SAP patients experience respiratory failure following an acute lung injury (ALI). Clinicians provide insufficient care for compounded ALI since the underlying pathophysiology is unknown. The mortality rate of SAP patients is severely impacted by it. OBJECTIVE: The study aims to provide insight into immune cells, specifically their roles and modifications during SAP and ALI, through a comprehensive literature review. The emphasis is on immune cells as a therapeutic approach for treating SAP and ALI. FINDINGS: Immune cells play an important role in the complicated pathophysiology ofSAP and ALI by maintaining the right balance of pro- and anti-inflammatory responses. Immunomodulatory drugs now in the market have low thepeutic efficacy because they selectively target one immune cell while ignoring immune cell interactions. Accurate management of dysregulated immune responses is necessary. A critical initial step is precisely characterizing the activity of the immune cells during SAP and ALI. CONCLUSION: Given the increasing incidence of SAP, immunotherapy is emerging as a potential treatment option for these patients. Interactions among immune cells improve our understanding of the intricacy of concurrent ALI in SAP patients. Acquiring expertise in these domains will stimulate the development of innovative immunomodulation therapies that will improve the outlook for patients with SAP and ALI.
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Lesión Pulmonar Aguda , Pancreatitis , Humanos , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/etiología , Pancreatitis/inmunología , Pancreatitis/terapia , Pancreatitis/patología , Pancreatitis/complicaciones , Páncreas/inmunología , Páncreas/patología , Pulmón/inmunología , Pulmón/patología , Animales , Inmunoterapia/métodosRESUMEN
Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of Ca2+ release-activated Ca2+ (CRAC) channels has been proposed as a potential treatment, and currently, a novel selective CRAC channel inhibitor CM4620 (Auxora, CalciMedica) is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here, we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 n m, have been studied against necrosis induced by bile acids, palmitoleic acid, or l-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 n m and palmitoleic acid starting from 1 n m. Combining CM4620 and galactose (1 m m) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acid-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced edema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 m m) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.
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Galactosa , Pancreatitis , Galactosa/farmacología , Animales , Pancreatitis/tratamiento farmacológico , Pancreatitis/patología , Ratones , Bloqueadores de los Canales de Calcio/farmacología , Cinacalcet/farmacología , Cinacalcet/uso terapéutico , Humanos , Masculino , Ácidos y Sales Biliares/metabolismo , Modelos Animales de Enfermedad , Necrosis/tratamiento farmacológico , Enfermedad Aguda , Ácidos Grasos MonoinsaturadosRESUMEN
OBJECTIVE: Acute pancreatitis (AP) stands as a frequent cause for clinical emergency hospital admissions. The X-box binding protein 1 (XBP1) was found to be implicated in pancreatic acinar cell apoptosis. The objective is to unveil the potential mechanisms governed by XBP1 and SIRT6 in the context of AP. METHODS: Caerulein-treated human pancreatic duct epithelial (HPDE) cells to establish an in vitro research model. The levels and regulatory role of SIRT6 in the treated cells were evaluated, including its effects on inflammatory responses, oxidative stress, apoptosis, and endoplasmic reticulum stress. The relationship between XBP1 and SIRT6 was explored by luciferase and ChIP experiments. Furthermore, the effect of XBP1 overexpression on the regulatory function of SIRT6 on cells was evaluated. RESULTS: Caerulein promoted the decrease of SIRT6 and the increase of XBP1 in HPDE cells. Overexpression of SIRT6 slowed down the secretion of inflammatory factors, oxidative stress, apoptosis level, and endoplasmic reticulum stress in HPDE cells. However, XBP1 negatively regulated SIRT6, and XBP1 overexpression partially reversed the regulation of SIRT6 on the above aspects. CONCLUSION: Our study illuminates the role of XBP1 in downregulating SIRT6 in HPDE cells, thereby promoting cellular injury. Inhibiting XBP1 or augmenting SIRT6 levels holds promise in preserving cell function and represents a potential therapeutic avenue in the management of AP.