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Liao Y, Zhang W, Huang Z, Yang L, Lu M. Diagnostic and prognostic value of miR-146b-5p in acute pancreatitis. Hereditas 2025; 162:93. [PMID: 40450371 DOI: 10.1186/s41065-025-00466-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 05/26/2025] [Indexed: 06/03/2025] Open
Abstract
OBJECTIVE MicroRNAs hold great potential as biomarkers for assessing the progression of acute pancreatitis (AP). This study aimed to explore the value of miR-146b-5p in the diagnosis and prognosis of AP patients. METHODS 110 AP patients were included and divided into 40 severe AP (SAP) patients and 70 non-SAP patients based on disease severity. Serum miR-146b-5p levels were measured using RT-qPCR. The diagnostic value of miR-146b-5p was evaluated utilizing ROC curves. Pearson correlation coefficient was employed to analyze the correlations between APACHEII, BISAP, and MCTSI scores and miR-146b-5p levels. The AP cell model was constructed by treating AR42J cells with deoxycholic acid (DCA), the proliferative capacity of cells was measured with CCK-8, apoptosis was measured by flow cytometry, and IL-6 and IL-8 protein levels were analyzed by ELISA. RESULTS Serum miR-146b-5p levels were decreased in SAP and unfavorable patients. Serum miR-146b-5p was able to effectively differentiate between SAP and non-SAP patients, and also effectively differentiate between unfavorable and favorable patients. MiR-146b-5p levels were significantly negatively correlated with APACHEII score (r=-0.6676), BISAP score (r=-0.5696), and MCTSI score (r=-0.5857). Furthermore, in the AP cell model, miR-146b-5p expression was down-regulated, proliferative capacity was diminished, apoptosis was increased, and IL-6 and IL-8 levels were elevated, but overexpression of miR-146b-5p partially reversed these changes. CONCLUSION miR-146b-5p expression is down-regulated in the serum of SAP patients and cells, and it has a good diagnostic effect. It may be a potential biomarker and therapeutic target for AP.
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Affiliation(s)
- Ying Liao
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Weiwei Zhang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Zhenfei Huang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Liu Yang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Mingjin Lu
- Supply Room, The Fifth People's Hospital of Ganzhou, No. 666, Dongjiangyuan Avenue, Shuixi Town, Zhanggong District, Ganzhou City, Jiangxi Province, 341000, China.
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Chen Z, Zheng R, Jiang H, Zhang X, Peng M, Jiang T, Zhang X, Shang H. Therapeutic efficacy of Xuebijing injection in treating severe acute pancreatitis and its mechanisms of action: A comprehensive survey. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156629. [PMID: 40101453 DOI: 10.1016/j.phymed.2025.156629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/25/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025]
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a life-threatening condition associated with high mortality and limited therapeutic options. Current management strategies focus on infection prevention, immune regulation, and anticoagulation. Xuebijing Injection (XBJ), a widely used traditional Chinese medicine-derived intravenous preparation, has shown promising therapeutic effects in SAP. Herein, we sought to evaluate clinical and preclinical evidence on XBJ to reveal its potential mechanisms of action, and provide insights to guide future research and clinical applications. METHODS We conducted a comprehensive survey of studies on XBJ in the treatment of SAP across PubMed, Embase, Cochrane Library, CBM, CNKI, Wanfang and VIP databases from their inception to March 21st, 2024. RESULTS A total of 239 studies were included, comprising 12 animal experiments, 7 systematic reviews, 220 clinical trials. Mechanistic studies suggest that XBJ downregulates the expression of inflammatory mediators, improves immune function, and alleviates oxidative stress via multiple signaling pathways, including the TLR4/NF-κB, p38-MAPK, HMGB1/TLR, TLR4/NF-κB, FPR1/NLRP3, and JAK/STAT pathways. These effects contribute to reducing organ damage. Compared to standard treatment, XBJ has more effective at reducing mortality and complications, improving overall clinical outcomes, shortening ventilator use time, and hospital stay in SAP patients. CONCLUSIONS Preclinical evidence and clinical trial data indicated that XBJ can simultaneously regulate inflammatory responses, immune function, microcirculatory disorders, oxidative stress, and apoptosis. However, further research is required to elucidate the specific mechanisms of action, clinical characteristics and safety of XBJ.
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Affiliation(s)
- Zhuo Chen
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing 100700, China
| | - Rui Zheng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing 100700, China; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton L8N 1Y3, Canada.
| | - Huiru Jiang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing 100700, China
| | - Xinyi Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing 100700, China
| | - Mengqi Peng
- Shandong Second Medical University, Weifang 261053, China
| | - Tong Jiang
- Binzhou medical university, YanTai 264000, China
| | - Xiaowei Zhang
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing 100700, China; Dong-Fang Hospital of Beijing University of Chinese Medicine, No. 6 The First District of Fang-Xing-Yuan, Fengtai District, Beijing100078, China.
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Louis M, Ayinde B, Gibson B. Spontaneous Splenic Rupture in Severe Acute Pancreatitis: A Rare Life-Threatening Complication and Its Successful Management. Cureus 2025; 17:e80354. [PMID: 40206930 PMCID: PMC11981545 DOI: 10.7759/cureus.80354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 03/10/2025] [Indexed: 04/11/2025] Open
Abstract
The severity of acute pancreatitis ranges from mild discomfort to severe illness with significant complications. While most cases resolve with supportive care, severe acute pancreatitis may lead to rare but serious issues such as spontaneous splenic rupture. A 46-year-old female with a history of alcohol use, hypertension, depression, and anxiety presented with persistent abdominal pain, nausea, and vomiting. Initial imaging revealed acute pancreatitis with peripancreatic fluid collections. Despite conservative management, her symptoms persisted. She experienced sudden worsening of abdominal pain and a significant drop in hemoglobin levels. Imaging confirmed a spontaneous splenic rupture with a large subcapsular hematoma and hemoperitoneum. She underwent splenic artery embolization to control the bleeding and received blood transfusions for anemia. Her condition improved with supportive care, and she was discharged with plans for outpatient follow-up. Spontaneous splenic rupture is a rare complication of acute pancreatitis resulting from the close anatomical relationship between the pancreas and spleen. Mechanisms behind it include direct enzymatic damage, pseudocyst extension, vascular injury, and increased pressure from splenic vein thrombosis. Early recognition is crucial for timely intervention. Clinicians should consider splenic complications when patients with pancreatitis exhibit sudden clinical deterioration or unexplained anemia. Prompt imaging and appropriate management can improve outcomes. Understanding the potential complications of severe pancreatitis is essential for effective patient care.
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Affiliation(s)
- Mena Louis
- General Surgery, Northeast Georgia Medical Center Gainesville, Gainesville, USA
| | - Bolaji Ayinde
- Internal Medicine, Northeast Georgia Medical Center Gainesville, Gainesville, USA
| | - Brian Gibson
- Trauma and Acute Care Surgery, Northeast Georgia Medical Center Gainesville, Gainesville, USA
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Kumbhar G, Kurien RT, Joseph AJ, Simon EG, Dutta AK, Goel A, Whitcomb D, DharChowdhury S. Neutrophil-to-Lymphocyte Ratio Differentiates Infections from Sterile Inflammation in First Week of Acute Pancreatitis. Dig Dis Sci 2025; 70:853-861. [PMID: 39746893 DOI: 10.1007/s10620-024-08812-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Differentiating infections from sterile inflammation is crucial in early AP management. AIM This study aimed to assess the capability of Neutrophil-to-Lymphocyte Ratio (NLR) and procalcitonin to differentiate between sterile inflammation and infections in the first week of AP and to analyze the source, microbiological profile, and impact of infections in AP. METHODS Consecutive patients presenting within 5 days of symptom onset were included. Microbiological profiles and serious adverse events (SAEs: in-hospital mortality or discharge in critical state) were analyzed. Blood count obtained at fever onset was used for calculating the NLR. The ability of NLR and procalcitonin to differentiate infections from sterile inflammation in the first week was assessed. RESULTS Of 505 AP patients, 150 developed fevers. 48 (32%) had sterile inflammation, while 102 (68%) had infections. Most patients (n = 98, 65.3%) developed fever during the first week of illness (sterile inflammation (n = 43) and infections (n = 55)). NLR demonstrated good accuracy in differentiating infections from sterile inflammation in the first week (AUROC 0.70, p = 0.001), outperforming procalcitonin (AUROC 0.54, p = 0.58). Within infections (n = 102), 44 (43.1%) had infected pancreatic necrosis, 68 (66.7%) had extra-pancreatic infections, and 10 (9.8%) had both. Lower respiratory tract infection was the most common extra-pancreatic infection. Of 54 patients with culture-positive infections, 36 (66.7%) had grown multidrug-resistant (MDR) organisms. Fungal isolates were identified in 5 patients. Patients with infections had higher SAE incidence (21.6% vs. 4.2%, p = 0.007) than those with inflammation. The SAE incidence was higher with MDR infections than those without MDR (37.5% vs. 9.3%, p < 0.01). CONCLUSIONS Infections in AP occur early in the course of illness. NLR could serve as a reliable biomarker to distinguish infections from sterile inflammation in the early course of AP, aiding timely management. Patients with MDR infections have higher serious adverse outcomes.
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Affiliation(s)
- Gauri Kumbhar
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Reuben Thomas Kurien
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - A J Joseph
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Ebby George Simon
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Amit Kumar Dutta
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - David Whitcomb
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Sudipta DharChowdhury
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India.
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Zhang T, Huang X, Feng S, Shao H. Lactate-Dependent HIF1A Transcriptional Activation Exacerbates Severe Acute Pancreatitis Through the ACSL4/LPCAT3/ALOX15 Pathway Induced Ferroptosis. J Cell Biochem 2025; 126:e30687. [PMID: 39676583 DOI: 10.1002/jcb.30687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 12/17/2024]
Abstract
Acute pancreatitis (AP) is a common emergency in the digestive system, and in severe cases, it can progress to severe acute pancreatitis (SAP), with a mortality rate of up to 30%, representing a dire situation. SAP in mice was induced by l-arginine (l-Arg). HE, IHC, WB and ELISA were used to study the role and regulation of HIF1A in SAP. At the same time, QPCR, WB, CHIP-QPCR and luciferase report were used to explore the specific mechanism of HIF1A regulation of SAP in vitro. The research results indicate that following SAP induction, the pancreatic tissue of mice exhibited significant glycolytic abnormalities, accompanied by a marked upregulation of HIF1A expression. This led to apparent damage in the pancreatic tissue, lungs, and kidneys. However, in sh-HIF1A mice, the degree of these injuries was significantly alleviated, along with a reduction in the production of inflammatory factors, oxidative products, and lipid peroxidation markers. This suggests that HIF1A plays a crucial role in the inflammatory and oxidative stress processes during SAP. Further exploration revealed that the absence or overexpression of HIF1A affects SAP by inducing ferroptosis through the ACSL4/LPCAT3/ALOX15 pathway. Notably, the elevated lactate level resulting from glycolytic abnormalities further enhances the histone lactylation in the HIF1A promoter region, thereby aggravating the expression of HIF1A. Lactate-dependent HIF1A transcriptional activation exacerbates severe acute pancreatitis through the ACSL4/LPCAT3/ALOX15 pathway induced ferroptosis.
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Affiliation(s)
- Tingyuan Zhang
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xiaopei Huang
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shengnan Feng
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Huanzhang Shao
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
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Yang SJ, Luo Y, Chen BH, Zhan LH. Screening and identification of the hub genes in severe acute pancreatitis and sepsis. Front Mol Biosci 2024; 11:1425143. [PMID: 39364223 PMCID: PMC11446880 DOI: 10.3389/fmolb.2024.1425143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/31/2024] [Indexed: 10/05/2024] Open
Abstract
Background Severe acute pancreatitis (SAP) is accompanied with acute onset, rapid progression, and complicated condition. Sepsis is a common complication of SAP with a high mortality rate. This research aimed to identify the shared hub genes and key pathways of SAP and sepsis, and to explore their functions, molecular mechanism, and clinical value. Methods We obtained SAP and sepsis datasets from the Gene Expression Omnibus (GEO) database and employed differential expression analysis and weighted gene co-expression network analysis (WGCNA) to identify the shared differentially expressed genes (DEGs). Functional enrichment analysis and protein-protein interaction (PPI) was used on shared DEGs to reveal underlying mechanisms in SAP-associated sepsis. Machine learning methods including random forest (RF), least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) were adopted for screening hub genes. Then, receiver operating characteristic (ROC) curve and nomogram were applied to evaluate the diagnostic performance. Finally, immune cell infiltration analysis was conducted to go deeply into the immunological landscape of sepsis. Result We obtained a total of 123 DEGs through cross analysis between Differential expression analysis and WGCNA important module. The Gene Ontology (GO) analysis uncovered the shared genes exhibited a significant enrichment in regulation of inflammatory response. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the shared genes were primarily involved in immunoregulation by conducting NOD-like receptor (NLR) signaling pathway. Three machine learning results revealed that two overlapping genes (ARG1, HP) were identified as shared hub genes for SAP and sepsis. The immune infiltration results showed that immune cells played crucial part in the pathogenesis of sepsis and the two hub genes were substantially associated with immune cells, which may be a therapy target. Conclusion ARG1 and HP may affect SAP and sepsis by regulating inflammation and immune responses, shedding light on potential future diagnostic and therapeutic approaches for SAP-associated sepsis.
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Affiliation(s)
- Si-Jiu Yang
- Department of Critical Care Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yan Luo
- Department of Critical Care Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Bao-He Chen
- Department of Critical Care Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Ling-Hui Zhan
- Department of Critical Care Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- The School of Clinical Medicine, Fujian Medical University, Fujian, China
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Hamo-Giladi DB, Fokra A, Sabo E, Kabala A, Minkov I, Hamoud S, Hadad S, Abassi Z, Khamaysi I. Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches. J Cell Mol Med 2024; 28:e18512. [PMID: 39248454 PMCID: PMC11382361 DOI: 10.1111/jcmm.18512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 09/10/2024] Open
Abstract
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.
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Affiliation(s)
- Dalit B Hamo-Giladi
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Ahmad Fokra
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Edmond Sabo
- Department of Pathology, Carmel Hospital, Haifa, Israel
| | - Aviva Kabala
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
| | - Irena Minkov
- Department of Pathology, Rambam Health Care Center, Haifa, Israel
| | - Shadi Hamoud
- Department of Internal Medicine E, Rambam Health Care Center, Haifa, Israel
| | - Salim Hadad
- Department of Pharmacy, Rambam Health Care Center, Haifa, Israel
| | - Zaid Abassi
- Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Haifa, Israel
- Department of Laboratory Medicine, Rambam Health Care Center, Haifa, Israel
| | - Iyad Khamaysi
- Department of Gastroenterology, Rambam Health Care Center, Haifa, Israel
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Liu Y, Cui H, Mei C, Cui M, He Q, Wang Q, Li D, Song Y, Li J, Chen S, Zhu C. Sirtuin4 alleviates severe acute pancreatitis by regulating HIF-1α/HO-1 mediated ferroptosis. Cell Death Dis 2023; 14:694. [PMID: 37865653 PMCID: PMC10590376 DOI: 10.1038/s41419-023-06216-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 09/26/2023] [Accepted: 10/10/2023] [Indexed: 10/23/2023]
Abstract
Acute pancreatitis (AP) is a common emergency of the digestive system and serious cases can develop into severe acute pancreatitis (SAP), which ortality rates up to 30%. Sirtuin4 (SIRT4) is a member of the sirtuin family, and plays a key role in inflammation and oxidative stress. However, the potential role of SIRT4 in SAP has yet to be elucidated. In the present study, we found that the expression level of SIRT4 in human AP was downregulated by screening a public database, suggesting that SIRT4 may play a role in AP. Subsequently, we used L-arginine (L-Arg) to induce SAP in SIRT4 knockout (SIRT4_KO) and SIRT4 overexpression (AAV_SIRT4) mice. The results showed that the pancreatic tissue injury and related lung and kidney injury were serious in SIRT4_KO mice after SAP induction, but were significantly reduced in AAV_SIRT4 mice. More importantly, we found that the levels of antioxidant factors GSH and SOD were decreased in SIRT4_KO mice, and the production of oxidative products and lipid peroxidation markers was increased, suggesting that SIRT4 was involved in inflammation and oxidative stress during SAP. Further studies showed that the absence or overexpression of SIRT4 affected the expression level of Hypoxia-inducible factor-1α (HIF-1α) after SAP induction, and regulated the expression of ferroptosis related proteins by mediating HIF-1α/HO-1 pathway. Collectively, our study revealed that SIRT4 plays a protective role in SAP by regulating the HIF-1α/HO-1 pathway to inhibit ferroptosis.
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Affiliation(s)
- Yanna Liu
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Huning Cui
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Chaopeng Mei
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Mengwei Cui
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qianqian He
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qiaofang Wang
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Dejian Li
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Yaodong Song
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Jiye Li
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Sanyang Chen
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China.
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
| | - Changju Zhu
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China.
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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10
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Huang L, Zeng Y, Duan L, Zhuang Q, Zhou Y, Wang L, Chen L, Liu X, Xiong Y. Optimal timing of free total rhubarb anthraquinones on immune regulation in rats with severe acute pancreatitis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116266. [PMID: 36806482 DOI: 10.1016/j.jep.2023.116266] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rhubarb is the peeled and dried root of Rheum palmatum L., Rheum tanguticum Maxim. ex Balf. or Rheum officinale Baill. Free total rhubarb anthraquinones (FTRAs) isolated and extracted from rhubarb display the beneficial effects of anti-inflammation and immunological modulation. The timing of immune regulation is a major problem in the immunotherapy for severe acute pancreatitis (SAP). several studies reported that FTRAs could reduce systemic inflammatory responses by inhibiting early immune overactivity in the gut in rats with SAP. But, the optimal timing of rhubarb and FTRAs administration is not clear in clinical practice. Therefore, the time window for the best efficacy of rhubarb and FTRAs in the treatment of SAP patients should be further elucidated. AIM OF THE STUDY The main purpose of the present study was to evaluate the efficacy and optimal timing of immune modulation with FTRAs in the treatment of SAP in rats. MATERIALS AND METHODS FTRAs (22.5, 45 and 90 mg/kg), Rhubarb (RHU) (900 mg/kg, positive control) or normal saline (vehicle control) were initiated at 0 (immediately), 48 and 72 h every 12 h for three times in total. The therapeutic effects of FTRAs and RHU on pancreas and intestinal tissues injury, secondary infection with pseudomonas aeruginosa (PA), amylase, lipase, D-lactic acid (DLA), endotoxin (ET), proinflammatory and anti-inflammatory cytokines, macrophages, dendritic cells and regulatory T cells (Tregs) in the blood, small intestine and/or mesenteric lymph node (MLN) were determined in rats with SAP after treatment. RESULTS The results showed that administration of FTRAs at 0 h was superior to 48 h and 72 h, which significantly protected the injury of pancreas and intestinal tissues, reduced the mortality induced by secondary infection with PA, decreased the levels of amylase, lipase, DLA, ET, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-8, IL-18 and Tregs, and increased the levels of IL-4, sTNF-αR, macrophages and dendritic cells, secretary immunoglobulin A (SIgA) in the blood and/or small intestinal tissues in rats with SAP. CONCLUSIONS In conclusion, our studies indicate that the treatment window of FTRAs for SAP is within 48 h of development, administration of FTRAs at the early stage (0 h, immune overreaction period) was the optimal time and superior to that of 48 h and 72 h for its therapeutic efficacy. The earlier the administration of FTRAs, the better the therapeutic efficacy. Therefore, our data may provide a scientific rationale for the clinical application and optimal timing of FTRAs in the treatment of SAP.
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Affiliation(s)
- Liqiang Huang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China; Department of Pharmacy, Second People's Hospital of Yibin, Yibin, 644000, China
| | - Yue Zeng
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Lingjing Duan
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Qian Zhuang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yejiang Zhou
- Department of Gastrointestinal Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Lulu Wang
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Li Chen
- Department of Pharmacy, Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xingyu Liu
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Yuxia Xiong
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China.
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11
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Chen Y, Chen L, Xu H, Cao R, Morisseau C, Zhang M, Shi Y, Hammock BD, Wang J, Zhuang J, Liu Z, Chen G. Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases. J Med Chem 2023; 66:2979-3009. [PMID: 36689364 PMCID: PMC9974930 DOI: 10.1021/acs.jmedchem.2c01996] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound G1 against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor α (TNF-α) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis.
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Affiliation(s)
- Yuanguang Chen
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Lu Chen
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Huashen Xu
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ruolin Cao
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Christophe Morisseau
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA
| | - Maoying Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yajie Shi
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Bruce D. Hammock
- Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA
| | - Jieru Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Junning Zhuang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhongbo Liu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Guoliang Chen
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
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12
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Huang P, Jia L. MicroRNA-28-5p as a potential diagnostic biomarker for chronic periodontitis and its role in cell proliferation and inflammatory response. J Dent Sci 2022; 17:1501-1509. [PMID: 36299340 PMCID: PMC9588829 DOI: 10.1016/j.jds.2022.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/28/2022] [Indexed: 11/28/2022] Open
Abstract
Background/purpose Recent studies have pointed to the crucial role of microRNAs (miRNAs) in chronic periodontitis (CP). This study investigated the regulation and potential mechanisms of miR-28-5p in CP patients and lipopolysaccharide (LPS)-induced periodontal ligament cells (PDLCs). Materials and methods 76 CP patients and 71 periodontally healthy subjects were included. RT-qPCR was employed to examine miR-28-5p and sphingosine kinase −1 (SPHK1) in subjects’ gingival sulcus fluid and PDLCs. The diagnostic performance was evaluated by measuring the area under the curve (AUC) of the receiver operating characteristic (ROC) analysis. Pearson correlation coefficient (r) was adopted to explore the statistical relation between indicators. PDLCs proliferation and inflammation factors were determined by CCK-8 and ELISA assay. The direct target gene was validated by a dual-luciferase reporter assay. Results miR-28-5p was lowly expressed in CP patients and LPS-induced PDLCs (P < 0.05). AUC for miR-28-5p was 0.937, which had certain diagnostic value. Additionally, miR-28-5p was negatively correlated with periodontal clinical indicators and inflammatory factors. Cell proliferation of PDLCs was inhibited and inflammation was promoted under LPS induction, however, elevated miR-28-5p diminished the effect of LPS (P < 0.05). SPHK1 acts as a miR-28-5p target and the elevation of SPHK1 caused by LPS treatment was inhibited by the increased miR-28-5p. Conclusion Present study revealed that miR-28-5p could be served as a potential diagnostic biomarker for CP. And miR-28-5p may participate in CP progression by targeting SPHK1 to regulate the proliferation and inflammation of PDLCs. This study may offer insights into CP treatment and diagnosis.
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Affiliation(s)
| | - Linghui Jia
- Corresponding author. Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, 246 Yangqiao Zhong Road, Fuzhou, Fujian, 350002, China. Fax: 86 0591 83700838.
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13
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Association of Genetic Variants in IL6 Gene (rs1800795) with the Concentration of Inflammatory Markers (IL-6, hs-CRP) and Superoxide Dismutase in the Blood of Patients with Acute Pancreatitis—Preliminary Findings. Genes (Basel) 2022; 13:genes13020290. [PMID: 35205334 PMCID: PMC8872489 DOI: 10.3390/genes13020290] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/26/2022] [Accepted: 01/29/2022] [Indexed: 11/17/2022] Open
Abstract
In the course of acute pancreatitis, interleukin-6 plays an important role as a mediator in the inflammatory response. The course of inflammatory disease is associated with intensive oxidative stress, which may activate transcription factors leading to gene-expression changes. Isoenzymes of superoxide dismutase are involved in the defense against free radicals. This study aimed to evaluate changes in IL-6 concentration and the concentration/activity of superoxide dismutase isoenzymes (SOD1, SOD2, and SOD3) in the blood of patients with acute pancreatitis (AP) in terms of rs1800795 polymorphism in the IL6 gene. In the smoking AP patients group with the GC and GG genotypes, the plasma SOD1 concentration was significantly higher (p = 0.0146 and p = 0.0250, respectively) than in patients with CC genotype for SNP rs1800795 in the IL6 gene. An increase in SOD1 concentration in erythrocytes of AP patients with GC genotypes was also demonstrated compared to the individuals from the group with GG genotype (p = 0.0408). Furthermore, a positive correlation between IL-6 and SOD1 concentrations in the plasma of AP patients with GC genotype for SNP rs1800795 was shown. These results indicate that SOD1 may play a protective role against oxidative damage induced by inflammation in the group of AP patients with GC genotype.
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14
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Maatman TK, Westfall-Snyder JA, Ceppa EP, House MG, Nakeeb A, Nguyen TK, Schmidt CM, Zyromski NJ. Necrotizing Pancreatitis from Hypertriglyceridemia: More Severe Disease? Dig Dis Sci 2021; 66:4485-4491. [PMID: 33464454 DOI: 10.1007/s10620-020-06766-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/06/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Necrotizing pancreatitis (NP) is caused by hypertriglyceridemia (HTG) in up to 10% of patients. Clinical experience suggests that HTG-NP is associated with increased clinical severity; objective evidence is limited and has not been specifically studied in NP. AIM The aim of this study was to critically evaluate outcomes in HTG-NP. We hypothesized that patients with HTG-NP had significantly increased severity, morbidity, and mortality compared to patients with NP from other etiologies. METHODS A case-control study of all NP patients treated at a single institution between 2005 and 2018 was performed. Diagnostic criteria of HTG-NP included a serum triglyceride level > 1000 mg/dL and the absence of another specific pancreatitis etiology. To control for differences in age, sex, and comorbidities, non-HTG and HTG patients were matched at a 4:1 ratio using propensity scores. Outcomes were compared between non-HTG and HTG patients. RESULTS A total of 676 NP patients were treated during the study period. The incidence of HTG-NP was 5.8% (n = 39). The mean peak triglyceride level at diagnosis was 2923 mg/dL (SEM, 417 mg/dL). After propensity matching, no differences were found between non-HTG and HTG patients in CT severity index, degree of glandular necrosis, organ failure, infected necrosis, necrosis intervention, index admission LOS, readmission, total hospital LOS, or disease duration (P = NS). Mortality was similar in non-HTG-NP (7.1%) and HTG-NP (7.7%), P = 1.0. CONCLUSION In this large, single-institution series, necrotizing pancreatitis caused by hypertriglyceridemia had similar disease severity, morbidity, and mortality as necrotizing pancreatitis caused by other etiologies.
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Affiliation(s)
- T K Maatman
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | | | - E P Ceppa
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - M G House
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - A Nakeeb
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - T K Nguyen
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - C M Schmidt
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA
| | - N J Zyromski
- Department of Surgery, Indiana University School of Medicine, 545 Barnhill Drive EH 519, Indianapolis, IN, 46202, USA.
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15
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Nalisa M, Nweke EE, Smith MD, Omoshoro-Jones J, Devar JWS, Metzger R, Augustine TN, Fru PN. Chemokine receptor 8 expression may be linked to disease severity and elevated interleukin 6 secretion in acute pancreatitis. World J Gastrointest Pathophysiol 2021; 12:115-133. [PMID: 34877026 PMCID: PMC8611186 DOI: 10.4291/wjgp.v12.i6.115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/08/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory disease, which presents with epigastric pain and is clinically diagnosed by amylase and lipase three times the upper limit of normal. The 2012 Atlanta classification stratifies the severity of AP as one of three risk categories namely, mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP). Challenges in stratifying AP upon diagnosis suggest that a better understanding of the underlying complex pathophysiology may be beneficial. AIM To identify the role of the chemokine receptor 8 (CCR8), expressed by T-helper type-2 Lymphocytes and peritoneal macrophages, and its possible association to Interleukin (IL)-6 and AP stratification. METHODS This study was a prospective case-control study. A total of 40 patients were recruited from the Chris Hani Baragwanath Academic Hospital and the Charlotte Maxeke Johannesburg Academic Hospital. Bioassays were performed on 29 patients (14 MAP, 11 MSAP, and 4 SAP) and 6 healthy controls as part of a preliminary study. A total of 12 mL of blood samples were collected at Day (D) 1, 3, 5, and 7 post epigastric pain. Using multiplex immunoassay panels, real-time polymerase chain reaction (qRT-PCR) arrays, and multicolour flow cytometry analysis, immune response-related proteins, genes, and cells were profiled respectively. GraphPad Prism™ software and fold change (FC) analysis was used to determine differences between the groups. P<0.05 was considered significant. RESULTS The concentration of IL-6 was significantly different at D3 post epigastric pain in both the MAP group and MSAP group with P = 0.001 and P = 0.013 respectively, in a multiplex assay. When a FC of 2 was applied to identify differentially expressed genes using RT2 Profiler, CCR8 was shown to increase steadily with disease severity from MAP (1.33), MSAP (38.28) to SAP (1172.45) median FC. Further verification studies using RT-PCR showed fold change increases of CCR8 in MSAP and SAP ranging from 1000 to 1000000 times when represented as Log10, compared to healthy control respectively at D3. The findings also showed differing lymphocyte and monocyte cell frequency between the groups. With monocyte population frequency as high as 70% in MSAP at D3. CONCLUSION The higher levels of CCR8 and IL-6 in the severe patients and immune cell differences compared to MAP and controls provide an avenue for exploring AP stratification to improve management.
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Affiliation(s)
- Mwangala Nalisa
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Ekene Emmanuel Nweke
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Martin D Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - Jones Omoshoro-Jones
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - John WS Devar
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
- Department of Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg 1864, Gauteng, South Africa
| | - Rebecca Metzger
- Institut für Immunologie, Ludwig-Maximilians-Universität München, München 80539, Germany
| | - Tanya N Augustine
- School of Anatomical Sciences, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
| | - Pascaline N Fru
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, Gauteng, South Africa
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16
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Machicado JD, Mounzer R, Paragomi P, Pothoulakis I, Hart PA, Conwell DL, de-Madaria E, Greer P, Yadav D, Whitcomb DC, Lee PJ, Hinton A, Papachristou GI. Rectal Indomethacin Does Not Mitigate the Systemic Inflammatory Response Syndrome in Acute Pancreatitis: A Randomized Trial. Clin Transl Gastroenterol 2021; 12:e00415. [PMID: 34704970 PMCID: PMC8553238 DOI: 10.14309/ctg.0000000000000415] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Experimental data suggest that nonsteroidal antiinflammatory drugs may prevent disease severity and mortality in acute pancreatitis (AP). The aim of this study was to compare the efficacy of rectal indomethacin vs placebo in reducing the systemic inflammatory response syndrome (SIRS) score in a high-risk AP population for clinical progression. METHODS We conducted a single-center, quadruple-blinded, randomized, placebo-controlled trial. Eligible criteria were subjects with AP and SIRS within 72 hours of presentation and those without organ failure. Subjects were allocated in a 1:1 ratio to indomethacin or placebo using simple randomization. Both interventions were administered rectally every 8 hours for 6 doses and compared using both intention-to-treat and per-protocol analyses. RESULTS A total of 42 subjects (mean age 52 years, 55% men) were randomized to indomethacin (n = 18) or placebo (n = 24). There was no significant difference between the indomethacin and placebo groups in the change of SIRS score, proportion of subjects with SIRS, and distribution of SIRS scores at 24, 48, and 72 hours from randomization. There were no significant differences in the change of C-reactive protein levels at 48 hours or clinical outcomes between both treatment groups. Indomethacin was as safe as placebo, with 2 adverse events occurring in the placebo and none in the indomethacin arm. DISCUSSION Rectal indomethacin can be safely administered over 48 hours; however, it is not superior to placebo in reducing the SIRS or clinical progression in a high-risk population with AP (ClinicalTrials.gov: NCT02692391).
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Affiliation(s)
- Jorge D. Machicado
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA;
| | - Rawad Mounzer
- Interventional Endoscopy Associates, Scottsdale, Arizona, USA;
| | - Pedram Paragomi
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Ioannis Pothoulakis
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Darwin L. Conwell
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Enrique de-Madaria
- Gastroenterology Department, Alicante University General Hospital, ISABIAL, Alicante, Spain;
| | - Phil Greer
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Peter J. Lee
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, the Ohio State University, Columbus, Ohio, USA.
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;
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Li Z, Wang H, Wu K, Zhang L. Omarigliptin protects against nonalcoholic fatty liver disease by ameliorating oxidative stress and inflammation. J Biochem Mol Toxicol 2021; 35:e22914. [PMID: 34533252 DOI: 10.1002/jbt.22914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 07/20/2021] [Accepted: 09/01/2021] [Indexed: 12/26/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disease with high morbidity. Omarigliptin is a novel antidiabetic drug that inhibits dipeptidyl peptidase-4 and alleviates inflammation and insulin resistance. In the present study, the anti-inflammatory and antioxidative stress property of omarigliptin will be investigated to explore the potential therapeutic effects of omarigliptin on NAFLD in mice models. A high-fat diet (HFD) was used to induce a NAFLD model in mice. Hematoxylin-eosin staining and detection on the concentrations of total cholesterol (TC) and triglyceride (TG) were used to evaluate lipid accumulation of the liver tissues. Liver function was evaluated by measuring aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. The insulin resistance index, the concentration of glucose, and insulin in the serum were determined. The levels of malondialdehyde and superoxide dismutase activities were detected to access the oxidative stress state. The concentrations of interleukin (IL)-1α, IL-6, and CXCL1 were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to determine the expression levels of nuclear factor kappa B (NF-κB) p65 and SIRT1 in the liver tissues. Significant elevated body weight and liver weight, marked macrovesicular steatosis combined with hepatocellular ballooning on the liver tissues, accumulated TC and TG concentrations, damaged liver function, increased oxidative stress, and elevated production of inflammatory factors were all induced with an HFD and significantly reversed by treatment with omarigliptin. Also, the activated NF-κB signaling pathway, as well as suppressed SIRT1 expression level, were significantly reversed by omarigliptin. Omarigliptin protected against NAFLD by ameliorating oxidative stress and inflammation.
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Affiliation(s)
- Zeyu Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hong Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Kanglin Wu
- Department of Emergency, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Lianfeng Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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18
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Mehta Y, Dixit SB, Zirpe K, Sud R, Gopal PB, Koul PA, Mishra VK, Ansari AS, Chamle VS. Therapeutic Approaches in Modulating the Inflammatory and Immunological Response in Patients With Sepsis, Acute Respiratory Distress Syndrome, and Pancreatitis: An Expert Opinion Review. Cureus 2021; 13:e18393. [PMID: 34692364 PMCID: PMC8526068 DOI: 10.7759/cureus.18393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2021] [Indexed: 12/15/2022] Open
Abstract
Immunomodulation has long been an adjunct approach in treating critically ill patients with sepsis, acute respiratory distress syndrome (ARDS), and acute pancreatitis (AP). Hyperactive immune response with immunopathogenesis leads to organ dysfunction and alters the clinical outcomes in critically ill. Though the immune response in the critically ill might have been overlooked, it has gathered greater attention during this novel coronavirus disease 2019 (COVID-19) pandemic. Modulating hyperactive immune response, the cytokine storm, especially with steroids, has shown to improve the outcomes in COVID-19 patients. In this review, we find that immune response pathogenesis in critically ill patients with sepsis, ARDS, and AP is nearly similar. The use of immunomodulators such as steroids, broad-spectrum serine protease inhibitors such as ulinastatin, thymosin alpha, intravenous immunoglobulins, and therapies such as CytoSorb and therapeutic plasma exchange may help in improving the clinical outcomes in these conditions. As the experience of the majority of physicians in using such therapeutics may be limited, we provide our expert comments regarding immunomodulation to optimize outcomes in patients with sepsis/septic shock, ARDS, and AP.
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Affiliation(s)
- Yatin Mehta
- Institute of Critical Care and Anesthesiology, Medanta - The Medicity, Gurugram, IND
| | | | - Kapil Zirpe
- Neurocritical Care, Grant Medical Foundation, Ruby Hall Clinic, Pune, IND
| | - Randhir Sud
- Institute of Digestive & Hepatobiliary Sciences, Medanta - The Medicity, Gurugram, IND
| | - Palepu B Gopal
- Department of Critical Care, Continental Hospitals, Hyderabad, IND
| | - Parvaiz A Koul
- Department of Pulmonary Medicine, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, IND
| | - Vijay K Mishra
- Medica Institute of Critical Care, Bhagwan Mahavir Medica Superspecialty Hospital, Ranchi, IND
| | - Abdul S Ansari
- Department of Critical Care Services, Nanavati Super Specialty Hospital, Mumbai, IND
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Pan L, Niu Z, Gao Y, Wang L, Liu Z, Liu J, Sun J, Pei H. Silencing of CREB Inhibits HDAC2/TLR4/NF-κB Cascade to Relieve Severe Acute Pancreatitis-Induced Myocardial Injury. Inflammation 2021; 44:1565-1580. [PMID: 33725236 DOI: 10.1007/s10753-021-01441-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 02/06/2021] [Accepted: 02/19/2021] [Indexed: 02/08/2023]
Abstract
The purpose of the present study is to investigate the role of CREB in cardiomyocytes proliferation in regulation of HDAC2-dependent TLR4/NF-κB pathway in severe acute pancreatitis (SAP)-induced myocardial injury. The SAP rat model was developed by injecting sodium touracholate into SD rats and then infected with lentivirus vectors expressing sh-CREB in the presence/absence of LPS. The pathological alterations of rat pancreatic and cardiac tissues were observed by HE staining. TUNEL assay was used to study apoptosis of cardiomyocytes. Next, the loss- and gain-function assay was conducted in LPS-induced myocardial injury cardiomyocytes to define the roles of CREB, HDAC2, and TLR4 in cardiomyocyte proliferation, apoptosis, inflammation, and myocardial injury in vitro. ChIP assay was used to study the enrichment of CREB bound to HDAC2 promoter. RT-qPCR and Western blot analysis were used to detect the expressions of related mRNA and proteins in the NF-κB pathway, respectively. CREB was found to be overexpressed in both SAP tissues and cells. CREB directly bound to the promoter of HDAC2 and activated its expression. Overexpressed CREB or HDAC2 inhibited proliferation and promoted apoptosis of cardiomyocytes. Suppression of CREB inhibited the HDAC2/TLR4/NF-κB cascade to promote proliferation and inhibit apoptosis of cardiomyocytes. The in vitro results were validated in vivo experiments. Coherently, suppression of CREB can inhibit HDAC2/TLR4/NF-κB cascade to promote cardiomyocyte proliferation, thus ameliorating SAP-induced myocardial injury.
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Affiliation(s)
- Longfei Pan
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China.
| | - Zequn Niu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Yanxia Gao
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Liming Wang
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Zhong Liu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Jie Liu
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Jiangli Sun
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
| | - Honghong Pei
- Department of Emergency, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xincheng District, 710004, Xi'an, Shaanxi Province, People's Republic of China
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20
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Forman MA, Steiner JM, Armstrong PJ, Camus MS, Gaschen L, Hill SL, Mansfield CS, Steiger K. ACVIM consensus statement on pancreatitis in cats. J Vet Intern Med 2021; 35:703-723. [PMID: 33587762 PMCID: PMC7995362 DOI: 10.1111/jvim.16053] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
Background Pancreatitis in cats, although commonly diagnosed, still presents many diagnostic and management challenges. Objective To summarize the current literature as it relates to etiology, pathogenesis, diagnosis, and management of pancreatitis in cats and to arrive at clinically relevant suggestions for veterinary clinicians that are based on evidence, and where such evidence is lacking, based on consensus of experts in the field. Animals None. Methods A panel of 8 experts in the field (5 internists, 1 radiologist, 1 clinical pathologist, and 1 anatomic pathologist), with support from a librarian, was formed to assess and summarize evidence in the peer reviewed literature and complement it with consensus clinical recommendations. Results There was little literature on the etiology and pathogenesis of spontaneous pancreatitis in cats, but there was much in the literature about the disease in humans, along with some experimental evidence in cats and nonfeline species. Most evidence was in the area of diagnosis of pancreatitis in cats, which was summarized carefully. In contrast, there was little evidence on the management of pancreatitis in cats. Conclusions and Clinical Importance Pancreatitis is amenable to antemortem diagnosis by integrating all clinical and diagnostic information available, and recognizing that acute pancreatitis is far easier to diagnose than chronic pancreatitis. Although both forms of pancreatitis can be managed successfully in many cats, management measures are far less clearly defined for chronic pancreatitis.
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Affiliation(s)
- Marnin A Forman
- Cornell University Veterinary Specialists, Stamford, Connecticut, USA
| | - Joerg M Steiner
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - P Jane Armstrong
- College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA
| | - Melinda S Camus
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Lorrie Gaschen
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Louisiana, USA
| | - Steve L Hill
- Flagstaff Veterinary Internal Medicine Consulting, Flagstaff, Arizona, USA
| | | | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
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21
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Tsaroucha A, Kaldis V, Vailas M, Schizas D, Lambropoulou M, Papalois A, Tsigalou C, Gaitanidis A, Pitiakoudis M, Simopoulos C. The positive effect of eugenol on acute pancreatic tissue injury: a rat experimental model. Pan Afr Med J 2021; 38:132. [PMID: 33912302 PMCID: PMC8052617 DOI: 10.11604/pamj.2021.38.132.20202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 01/20/2021] [Indexed: 11/18/2022] Open
Abstract
Introduction we present a rat experimental model used to evaluate the possible reduction in the extent of pancreatic tissue injury in acute pancreatitis cases, after administration of eugenol. Methods one hundred and twenty Wistar rats were used, which were randomly assigned in 3 groups: sham (n=20), control (n=50) and eugenol (n=50). Acute pancreatitis was induced by biliopancreatic ligation in the control and eugenol groups, but not in the Sham group. In the eugenol group, eugenol was administered per-os. Five histopathological parameters, such as edema, inflammatory infiltration, duct dilatation, hemorrhage and acinar necrosis were evaluated. Results at 72 h from acute pancreatitis induction, the total histological score was diminished in the eugenol group (p<0.0005) and duct dilatation and inflammatory infiltration were reduced compared to the control group (p<0.05). In addition, at 72 h, eugenol reduced pancreatic myeloperoxidase activity (p<0.0005). Conclusion eugenol, a highly free radical scavenger agent, may have a preventive role in acute pancreatic injury, as it was evident in our rat experimental model.
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Affiliation(s)
- Alexandra Tsaroucha
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,2nd Department of Surgery and Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Vasileios Kaldis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Michail Vailas
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,First Department of Surgery, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,First Department of Surgery, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Lambropoulou
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,Laboratory of Histology-Embryology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Apostolos Papalois
- Experimental-Research Department, ELPEN Pharmaceuticals, Pikermi, Attica, Greece
| | - Christina Tsigalou
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,Laboratory of Microbiology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Apostolos Gaitanidis
- 2nd Department of Surgery and Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Michael Pitiakoudis
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,2nd Department of Surgery and Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Constantinos Simopoulos
- Postgraduate Program in Hepatobiliary/Pancreatic Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.,2nd Department of Surgery and Laboratory of Experimental Surgery, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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22
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IL-10-1082G>A polymorphism, use of opioids and age affect the course of acute pancreatitis. Eur J Gastroenterol Hepatol 2021; 32:178-185. [PMID: 32804849 DOI: 10.1097/meg.0000000000001875] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We aimed to determine the association of two of the most important functional polymorphisms of IL-8 and IL-10 with the clinical course and outcome of acute pancreatitis. METHOD Ninety-three patients with acute pancreatitis were genotyped for IL-8-251T>A and IL-10-1082G>A using PCR-RFLP. The severity of the disease was determined based on the Atlanta Classification system. RESULTS In patients treated with opioids, the odds for severe form of acute pancreatitis, its complications, and death were increased. Advanced age was associated with higher odds of organ/multiple organ failure and other systemic complications. Multivariate logistic regression analyses confirmed the observed effect of age and use of opioids, and revealed higher odds for the development of severe form of acute pancreatitis [P = 0.017, odds ratio (OR): 4.324, 95% confidence interval (CI): 1.305-14.323], its complications in general (P = 0.011, OR: 4.936, 95% CI: 1.442-16.897), pancreatic necrosis (P = 0.032, OR: 3.922, 95% CI: 1.122-13.707) and systemic inflammatory response syndrome (P = 0.037, OR: 3.838, 95% CI: 1.085-13.583) in the absence of IL-10-1082G>A variant allele. The effect of IL-8 -251T>A on acute pancreatitis severity or mortality was not detected. CONCLUSION Our study suggests the IL-10 -1082A allele as a protective factor in acute pancreatitis. Opioid analgesics treatment in acute pancreatitis is associated with severity, complications and mortality, while advanced age increases the risk of systemic complications.
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Puentes-Pardo JD, Moreno-SanJuan S, Carazo Á, León J. Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease. Antioxidants (Basel) 2020; 9:antiox9121214. [PMID: 33276470 PMCID: PMC7760122 DOI: 10.3390/antiox9121214] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022] Open
Abstract
Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system.
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Affiliation(s)
- Jose D. Puentes-Pardo
- Research Unit, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain
- Department of Pharmacology, Faculty of Pharmacy, University of Granada, 18011 Granada, Spain
- Correspondence: (J.D.P.-P.); (J.L.); Tel.: +34-958-023-706 (J.L.)
| | - Sara Moreno-SanJuan
- Cytometry and Microscopy Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain;
| | - Ángel Carazo
- Genomic Research Service, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain;
| | - Josefa León
- Research Unit, Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 18012 Granada, Spain
- Clinical Management Unit of Digestive Disease, San Cecilio University Hospital, 18016 Granada, Spain
- Correspondence: (J.D.P.-P.); (J.L.); Tel.: +34-958-023-706 (J.L.)
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24
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Kuzi S, Mazaki-Tovi M, Suchodolski JS, Rimer D, Lidbury JA, Steiner JM, Buono A, Nivy R, Segev G, Aroch I. Protease inhibitors, inflammatory markers, and their association with outcome in dogs with naturally occurring acute pancreatitis. J Vet Intern Med 2020; 34:1801-1812. [PMID: 32893923 PMCID: PMC7517856 DOI: 10.1111/jvim.15895] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 08/15/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022] Open
Abstract
Background Acute pancreatitis (AP) presumably is associated with pancreatic protease activation, protease inhibitor (PI) depletion, and inflammatory mediator secretion. Objectives Examine PIs and inflammatory mediator concentrations in dogs with AP and their association with death. Animals Thirty‐one dogs diagnosed with AP based on clinical signs, ultrasonographic findings, and increased canine pancreatic lipase immunoreactivity (cPLI) and 51 healthy control dogs. Methods Antithrombin and α2‐antiplasmin activity (ATA and α2AP, respectively) and concentrations of α1‐proteinase inhibitor (α1PI), α2‐macroglobulin (α2MG), C‐reactive protein (CRP), interleukins (ILs)‐2,6,8 and tumor necrosis factor‐α (TNF‐α) were prospectively measured. Severity of AP was assessed by clinical severity scoring systems. Results Mortality rate was 19%. Antithrombin activity was lower (P = .004) and maximal CRP, IL‐6, and TNF‐α concentrations higher (P < .04) in the AP group compared to the controls, whereas IL‐2, IL‐8, α1PI, and α2AP concentrations did not differ between groups. Serum α2MG concentration was not reliably detected. Serum cPLI, CRP, and IL‐6 concentrations were significantly and positively correlated. The ATA was lower (P = .04), and canine acute pancreatitis severity (CAPS) scores higher (P = .009) in nonsurvivors compared to survivors. Higher CAPS scores were associated (P < .05) with decreased ATA and increased cPLI, CRP, and IL‐6 concentrations. Conclusions and Clinical Importance Systemic inflammation in dogs with AP is manifested by increased inflammatory mediator concentrations, correlating with cPLI and CRP concentrations. Hypoantithrombinemia is associated with death. Serum concentrations of α2AP and α1PI are less useful prognostic markers. The CAPS score is a useful prognostic marker in dogs with AP.
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Affiliation(s)
- Sharon Kuzi
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Michal Mazaki-Tovi
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Jan S Suchodolski
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Dar Rimer
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Jonathan A Lidbury
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Joerg M Steiner
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Agostino Buono
- Gastrointestinal Laboratory, Texas A&M University, College Station, Texas, USA
| | - Ran Nivy
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Gilad Segev
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Itamar Aroch
- Department of Small Animal Internal Medicine, The Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
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25
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Heath H, Britton G, Kudo H, Renney G, Ward M, Hutchins R, Foster GR, D Goldin R, Alazawi W. Stat2 loss disrupts damage signalling and is protective in acute pancreatitis. J Pathol 2020; 252:41-52. [PMID: 32506441 DOI: 10.1002/path.5481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 05/16/2020] [Accepted: 05/29/2020] [Indexed: 12/15/2022]
Abstract
The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected i.p. with caerulein or l-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and l-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels, including TNF-α and IL-10, and reduced NF-κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-α improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNF-α expression, but not histological injury or serum amylase. WT/Stat2-/- bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow-derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Helen Heath
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Gary Britton
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Hiromi Kudo
- Department of Cellular Pathology, Imperial College, London, UK
| | - George Renney
- Proteomics, Institute of Psychiatry, Kings College London, London, UK
| | - Malcolm Ward
- Proteomics, Institute of Psychiatry, Kings College London, London, UK
| | - Robert Hutchins
- Hepatopancreaticobiliary Unit, Barts Health NHS Trust, London, UK
| | - Graham R Foster
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Robert D Goldin
- Department of Cellular Pathology, Imperial College, London, UK
| | - William Alazawi
- Blizard Institute, Queen Mary, University of London, London, UK
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Chen Z, Dong WH, Wu Q, Wang J. Two-layer regulation of TRAF6 mediated by both TLR4/NF-kB signaling and miR-589-5p increases proinflammatory cytokines in the pathology of severe acute pancreatitis. Am J Transl Res 2020; 12:2379-2395. [PMID: 32655778 PMCID: PMC7344107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/24/2020] [Indexed: 06/11/2023]
Abstract
Inflammation is a leading cause of severe acute pancreatitis (SAP). MicroRNAs (miRNAs) are emerging as important regulators involved in the pathogenesis of many diseases including pancreatitis. To identify miRNAs that contribute to the pathology of SAP, we carried out a miRNA-specific microarray analysis using the biopsies donated by SAP patients. We totally obtained 50 differentially expressed miRNAs, including 20 upregulated and 30 downregulated miRNAs, respectively. We focused our current study on revealing the downstream target and the upstream regulatory mechanism of miR-589-5p, the most downregulated miRNA in our candidate lists. Our prediction results indicated that miR-589-5p might target TRAF6 (tumor necrosis factor receptor-associated factor 6), a critical member of the TLR4/NF-kB (Toll-like receptor 4/nuclear transcription factor-kB) pathway. Using different strategies such as in vitro overexpression or downregulation of miR-589-5p and treatment with lipopolysaccharide (LPS), we found that the expression of TRAF6 was regulated by two-layer mechanisms. On the one hand, TRAF6 was transcriptionally controlled by a DNA methylation mediated downregulation of miR-589-5p. On the other hand, the activation of TLR4/NF-kB signaling also could increase the protein level of TRAF6. The increased TRAF6 aggravated the downstream signaling and caused the translocation of NF-kB subunits from the cytoplasm to the nucleus, where NF-kB transcription factors induced the expression of proinflammatory cytokine genes. The maturation and production of proinflammatory cytokines induced inflammatory response and caused the occurrence of SAP.
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Affiliation(s)
- Zhi Chen
- Department of Critical Care Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang UniversityNanchang, Jiangxi, China
| | - Wei-Hua Dong
- Department of Critical Care Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang UniversityNanchang, Jiangxi, China
| | - Qi Wu
- Department of Critical Care Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang UniversityNanchang, Jiangxi, China
| | - Jun Wang
- Department of General Surgery, Jiangxi Provincial People’s Hospital Affiliated to Nanchang UniversityNanchang, Jiangxi, China
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Abstract
OBJECTIVES Severe acute pancreatitis (SAP) is still a big challenge. Accumulated data showed that overexpression of cyclooxygenase-2 (COX-2) in acute pancreatitis and experimental pancreatitis could be attenuated with COX-2 inhibitors. This study was aimed to evaluate whether the occurrence of SAP could be prevented by selective COX-2 inhibitors. METHODS A total of 190 patients with predicted SAP were randomized into convention group or convention plus COX-2 inhibitors (C+COX-2-Is) group. Besides conventional treatment to all patients in 2 groups, parecoxib (40 mg/d intravenous injection for 3 days) and celecoxib (200 mg oral or tube feeding twice daily for 7 days) were sequentially administrated to the patients in the C+COX-2-Is group. The primary outcome was predefined as the occurrence of SAP. The serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) for all of the patients were measured. RESULTS The occurrence of SAP in the C+COX-2-Is group was decreased 47.08% compared with the convention group, 21.05% (20/95) vs 39.78% (37/93), P = 0.005. A reduction of late local complications was also shown in the C+COX-2-Is group, 18.95% (18/93) vs 34.41% (32/95), P = 0.016. The serum levels of IL-6 and TNF-α were significantly lower in the C+COX-2-Is group than those in the convention group, P < 0.05. Parecoxib relieved abdominal pain more rapidly and decreased the consumption of meperidine. An incremental reduction of cost for 1% decrease of SAP occurrence was RMB475. DISCUSSION Sequential administration of parecoxib and celecoxib in patients with predicted SAP obtained about half-reduction of SAP occurrence through decreasing serum levels of TNF-α and IL-6. This regimen presented good cost-effectiveness.
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28
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Ćeranić DB, Zorman M, Skok P. Interleukins and inflammatory markers are useful in predicting the severity of acute pancreatitis. Bosn J Basic Med Sci 2020; 20:99-105. [PMID: 31242405 PMCID: PMC7029213 DOI: 10.17305/bjbms.2019.4253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP) is a disease with significant morbidity and mortality. The aim of this study was to evaluate the predictive role of inflammatory markers, particularly interleukins (ILs), in the course of AP and to determine the frequency of etiologic factors of AP. We included patients with AP who were treated at our institution from May 1, 2012 to January 31, 2015. Different laboratory parameters, including ILs, and the severity scoring systems Ranson's criteria and Bedside Index of Severity in Acute Pancreatitis (BISAP) were analyzed. AP was classified into mild and severe, and independent parameters were compared between these groups. The predictive performance of each parameter was evaluated using receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC). A binomial logistic regression was performed to evaluate Ranson's criteria and IL6, IL8, and IL10 (at admission and after 48 hours) in the course of AP. Overall, 96 patients were treated, 59 (61.5%) males and 37 (38.5%) females, average age 62.5 ± 16.8 years (range 22-91 years). The best predictor for the severity of AP was IL6, measured 48 hours after admission (AUC = 0.84). Other useful predictors of the severity of AP were lactate dehydrogenase (p < 0.001), serum glucose (p < 0.006), and difference in the platelet count (p < 0.001) between admission and after 48 hours (p < 0.001), hemoglobin (p < 0.027) and erythrocytes (p < 0.029). The major causes of AP were gallstones and alcohol consumption. According to our results, IL6 and Ranson score are important predictors of the severity of AP.
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Affiliation(s)
- Davorin Branislav Ćeranić
- Department of Gastroenterology, Division of Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia.
| | - Milan Zorman
- Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor, Slovenia.
| | - Pavel Skok
- Department of Gastroenterology, Division of Internal Medicine, University Medical Centre Maribor; Faculty of Medicine, University of Maribor, Maribor, Slovenia.
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Sundar V, Senthil Kumar KA, Manickam V, Ramasamy T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review. J Pharm Pharmacol 2020; 72:761-775. [DOI: 10.1111/jphp.13229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Objectives
Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death.
Key findings
We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases.
Summary
Since AP results from perturbations of multiple signaling pathways, the so called “monotargeted smart drugs” of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.
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Affiliation(s)
- Vaishnavi Sundar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | | | - Venkatraman Manickam
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Tamizhselvi Ramasamy
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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Munir F, Jamshed MB, Shahid N, Hussain HM, Muhammad SA, Mamun AA, Zhang Q. Advances in immunomodulatory therapy for severe acute pancreatitis. Immunol Lett 2020; 217:72-76. [DOI: 10.1016/j.imlet.2019.11.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/24/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023]
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Chung WS, Lin CL. Association between venous thromboembolism and acute pancreatitis: An analysis from the nationwide inpatient sample. CLINICAL RESPIRATORY JOURNAL 2019; 14:320-327. [PMID: 31846214 DOI: 10.1111/crj.13134] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 09/21/2019] [Accepted: 12/03/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS Acute inflammation of the pancreas may trigger a systemic inflammatory response and initiate coagulation. Few studies have been conducted on the association between venous thromboembolism (VTE) and acute pancreatitis (AP). We investigated the incidence and risk of VTE in patients with AP. METHODS We conducted a retrospective cohort analysis for the nationwide AP cohort. We identified 91 786 patients with AP and 183 557 controls who were frequency-matched according to sex, age (5-y interval), and index year from the National Health Insurance Research Database between 2000 and 2008. The patients and controls were followed until diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE), death or the end of 2011. RESULTS The nationwide cohort study showed that patients with AP exhibited a higher incidence of VTE (13.1 vs 5.65 per 10 000 person-y) than did the controls. After covariates were controlled for, the patients with AP had a 1.88-fold higher risk of VTE than did the controls (adjusted hazard ratios [aHR] = 1.88; 95% confidence intervals [CI] = 1.68-2.10). The incidence rates of DVT and PE were higher in the patients with AP than in the controls, irrespective of sex, age or comorbidity. The patients with AP exhibited a 1.86-fold higher aHR of DVT (95% CI = 1.63-2.12) and a 1.92-fold higher aHR of PE (95% CI = 1.59-2.31) than did the controls. CONCLUSION Patients with AP exhibited a significantly higher risk of VTE than did the controls.
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Affiliation(s)
- Wei-Sheng Chung
- Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.,Department of Health Services Administration, China Medical University, Taichung, Taiwan.,Department of Healthcare Administration, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
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Kuzi S, Mazor R, Segev G, Nivy R, Mazaki-Tovi M, Chen H, Rimer D, Duneyevitz A, Yas E, Lavy E, Aroch I. Prognostic markers and assessment of a previously published clinical severity index in 109 hospitalised dogs with acute presentation of pancreatitis. Vet Rec 2019; 187:e13. [PMID: 31662578 DOI: 10.1136/vr.105364] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 10/07/2019] [Accepted: 10/09/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) is common in dogs. Nevertheless, validated clinical severity index (CSI) scoring systems to assess severity and guide treatment in current, large-scale studies are unavailable. METHODS This is a retrospective study including 109 dogs. Pancreatitis was diagnosed based on clinical signs, abdominal sonographic evidence, positive pancreatic lipase assays and experts' assessment consensus. RESULTS The survival rate was 75 per cent (82 dogs). Azotaemia and presence of local complications (ie, ascites) and secondary complications (ie, acute kidney injury and acute respiratory distress syndrome) were significantly associated with death. In agreement with the previously published CSI, respiratory anomalies were significantly associated with death. However, in disagreement with that study, high scores in the kidney and local abdominal complication categories and the sum of scores of all nine categories, but not high gastrointestinal category score, were also significantly associated with death. A final CSI score of at least 4 was associated with death. CONCLUSIONS This study has validated a nine-category CSI, proven a useful assessment tool in dogs with AP. Several previously reported and novel prognostic markers were assessed.
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Affiliation(s)
- Sharon Kuzi
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Reut Mazor
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Gilad Segev
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Ran Nivy
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Michal Mazaki-Tovi
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Hilla Chen
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Dar Rimer
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Asia Duneyevitz
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Einat Yas
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Eran Lavy
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
| | - Itamar Aroch
- Internal Medicine, Hebrew University of Jerusalem Koret School of Veterinary Medicine, Rehovot, Israel
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Zhang X, Gao B, Huang Y, Zhang Y, Li Z, Zhao D, Ma B, Xue D, Zhang W. miR‑92a‑3p regulates trypsinogen activation via Egr1 in AR42J cells. Mol Med Rep 2019; 20:4140-4150. [PMID: 31545429 PMCID: PMC6797994 DOI: 10.3892/mmr.2019.10673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 07/15/2019] [Indexed: 12/29/2022] Open
Abstract
Acute pancreatitis (AP) exhibits high morbidity and mortality rates. The onset of AP is characterized by early trypsinogen activation. The present study aimed to investigate the expression of microRNA (miR)-92a-3p and early growth response protein 1 (Egr1), and the effect of miR-92a-3p on trypsinogen activation in the pancreatic exocrine cell line AR42J. mRNA and miRNA microarrays were used to identify differentially expressed mRNAs and miRNAs in AR42J cells. A miRNA-mRNA network was constructed using bioinformatics software, and Egr1 and its regulated miRNA subnetworks were identified by reviewing previous literature. The results suggested that miR-92a-3p could bind to Egr1 3′untranslated region sequence. Subsequently, miR-92a-3p mimic and inhibitor were used to transfect AR42J cells. Following transfection, reverse transcription-quantitative PCR and western blotting were performed to detect Egr1 expression. Furthermore, AR42J cells were cotransfected with miR-92a-3p inhibitor and small interfering (si)-Egr1. The trypsinogen activation rate of AR42J cells was measured by flow cytometry. Microarrays and bioinformatics results indicated that Egr1 may be a target gene of miR-92a-3p. In addition, the present study suggested that miR-92a-3p downregulated Egr1 in vitro and that miR-92a-3p and Egr1 expression was associated with trypsinogen activation. Furthermore, miR-92a-3p inhibitor reversed the effect of si-Egr1 on trypsinogen activation. In conclusion, miR-92a-3p may negatively regulate the activation of trypsinogen in AR42J cells via Egr1.
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Affiliation(s)
- Xueming Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Bo Gao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yang Huang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yong Zhang
- Department of Hepatopancreatobiliary Surgery, Weifang Traditional Chinese Medicine Hospital, Weifang, Shandong 261041, P.R. China
| | - Zhituo Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dali Zhao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Biao Ma
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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Ruiz-Rebollo ML, Muñoz-Moreno MF, Mayo-Iscar A, Udaondo-Cascante MA, Nistal RB. Statin intake can decrease acute pancreatitis severit. Pancreatology 2019; 19:807-812. [PMID: 31378582 DOI: 10.1016/j.pan.2019.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/18/2019] [Accepted: 07/21/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND/OBJECTIVES Acute Pancreatitis (AP) is one of the leading gastrointestinal conditions requiring hospitalization. It has been suggested that statins could exert a protective role in the natural history of AP; however, their influence is not entirely clear. Our objective was to investigate the relationship between statin intake and AP. METHODS Retrospective analysis of a prospective registry of patients diagnosed with AP. Statin intake on admission as well as clinical, analytical, demographic and radiological data were recorded. OUTCOME PARAMETERS Severity of AP, SIRS development, organ failure, local complications, intensive care admission, collection drainage, hospital length of admission, and death. Univariate and multivariate analyses as well as a propensity score logistic regression were conducted. RESULTS From March 2014-October 2018 we studied 356 patients. 101 patients (28%) were taking statins. 55 (15%) suffered from moderate/severe pancreatitis. Multivariate analysis showed a 50% less risk of suffering from moderate/severe AP (OR 0.50 95% CI 0.22-1.0, p 0.50) and 33% less risk of developing local complications (OR 0.33 95%CI 0.15-0.80, p 0.014) among statin consumers, with a tendency towards less SIRS. Propensity score analysis confirmed that patients on statins suffering from AP had a lower risk to have a moderate/severe episode (OR 0.409 95%CI 0.192-0.872, p 0.031), to develop local complications (OR 0.47 95%CI 0.20-1.06, p 0.11) and SIRS (OR 0.516 95% CI 0.28-0.93, p 0.041). CONCLUSIONS Patients taking statins who suffer from an episode of AP are more likely to follow a mild course and have a lower risk of developing local complications and SIRS.
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Affiliation(s)
| | | | - Agustín Mayo-Iscar
- Statistics Department, School of Medicine, University of Valladolid, Valladolid, Spain
| | | | - Reyes Busta Nistal
- Hepato-Gastroenterology Department, Hospital Clínico Universitario, Valladolid, Spain
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Mallick B, Tomer S, Arora SK, Lal A, Dhaka N, Samanta J, Sinha SK, Gupta V, Yadav TD, Kochhar R. Change in serum levels of inflammatory markers reflects response of percutaneous catheter drainage in symptomatic fluid collections in patients with acute pancreatitis. JGH Open 2019; 3:295-301. [PMID: 31406922 PMCID: PMC6684513 DOI: 10.1002/jgh3.12158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Percutaneous catheter drainage (PCD) is used as the first step in the management of symptomatic fluid collections in patients with acute pancreatitis (AP). There are limited data on the effect of PCD on inflammatory markers. AIM To study the effects of PCD on serum levels of C-reactive protein (CRP), IL-6, and IL-10 and its correlation with the outcome. METHODS Consecutive patients of AP with symptomatic fluid collections undergoing PCD were evaluated for serum levels of CRP, IL-6, and IL-10 before PCD and at 3 and 7 days after PCD. Resolution of organ failure (OF), sepsis, and pressure symptoms was considered to demonstrate the success of PCD. Changes in levels following PCD were correlated with outcome. RESULTS Indications of PCD in 59 patients (age 38.9 ± 13.17 years, 49 male) were suspected/documented infected pancreatic necrosis (n = 45), persistent OF (n = 40), and pressure symptoms (n = 7). A total of 49 (83.1%) patients improved with PCD, five patients required surgery, and six died. A significant difference was noted between baseline levels of CRP (P = 0.026) and IL-6 (P = 0.013) among patients who improved compared to those who worsened following PCD. Significant decrease (P < 0.01) of all three markers on day 3 of PCD insertion, with further decrease (P < 0.01) on day 7, was noted. The percentage of the decrease of IL-6 levels on day 3 and of CRP on day 7 correlated with the outcome. CONCLUSION PCD is associated with a significant decrease in CRP, IL-6, and IL-10 levels. Percentage decrease in IL-6 on day 3 and CRP on day 7 correlated with the outcome of patients managed with PCD.
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Affiliation(s)
- Bipadabhanjan Mallick
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Shallu Tomer
- Department of ImmunopathologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Sunil K Arora
- Department of ImmunopathologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Anupam Lal
- Department of RadiodiagnosisPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Narendra Dhaka
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Jayanta Samanta
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Saroj K Sinha
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Vikas Gupta
- Department of General SurgeryPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Thakur Deen Yadav
- Department of General SurgeryPostgraduate Institute of Medical Education and ResearchChandigarhIndia
| | - Rakesh Kochhar
- Department of GastroenterologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
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Grupp K, Bonk S, Poppe A, Wodack K, Reeh M, Gocht A, Mann O, Izbicki JR, Bachmann K. Cholecystokinin-8 treatment reduces acinar necrosis and edema of pigs with induced pancreatitis. Asian J Surg 2019; 43:272-277. [PMID: 31171354 DOI: 10.1016/j.asjsur.2019.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 04/11/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Acute pancreatitis is an inflammatory process of the pancreas and a leading cause of hospitalization amongst gastrointestinal disorders. Previously, cholecystokinin (CCK) has been described to play a role in regeneration of pancreas. The aim of this study was to analyse the function of cholecystokinin octapeptide (CCK-8) during induced pancreatitis in an animal model. METHODS Overall acute pancreatitis was induced in 38 pigs. After the induction of acute pancreatitis, half of the animals were treated with CCK-8. Intraoperative clinical data, postoperative blood parameters, 'Porcine Well-being' (PWB) and fitness score and post-mortal histopathological data were analysed. RESULTS At baseline, physiologically parameters of the pigs of both groups were comparable. No differences were observed regarding the overall survival of animals (p = 0.97). Postoperative PWB score were significantly enhanced in animals treated with CCK-8 as compared to the control group (p = 0.029). Moreover, histopathological analysis of the pancreatic tissue revealed that acinar necrosis and edema were significant reduced in the CCK-8 group in comparison to the control group (p = 0.016 and p = 0.019). CONCLUSIONS In conclusion, we found that CCK-8 treatment reduces acinar necrosis and edema of pancreatic tissue after induction of an acute pancreatitis in pigs.
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Affiliation(s)
- Katharina Grupp
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Sarah Bonk
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Annika Poppe
- Centre of Anesthesiology and Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Karin Wodack
- Centre of Anesthesiology and Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Reeh
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Gocht
- Institute of Anatomy and Experimental Morphology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Mann
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Bachmann
- Department of General-, Visceral- and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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Marek G, Ściskalska M, Grzebieniak Z, Milnerowicz H. Decreases in Paraoxonase-1 Activities Promote a Pro-inflammatory Effect of Lipids Peroxidation Products in Non-smoking and Smoking Patients with Acute Pancreatitis. Int J Med Sci 2018; 15:1619-1630. [PMID: 30588185 PMCID: PMC6299411 DOI: 10.7150/ijms.27647] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 01/06/2023] Open
Abstract
Aim: The study investigated the extent to which tobacco smoke exposure causes changes in lipids biochemistry through measurement blood concentrations of: paraoxonase-1 (PON-1) activities as lipid-bound enzyme into cell membrane, concentration of malonyldialdehyde (MDA), protein adducts of 4-hydroxynonenal (HNE-adducts), oxidized low density lipoproteins (oxLDL), total cholesterol (CH) and high-density lipoprotein cholesterol (HDL). Additionally, the activity of P isoform of glutathione S-transferase (GST-π) was measured. Methods: Investigations were performed in the blood of patients with acute pancreatitis (AP) on the 1st, 3rd and 7th day of hospitalization and in healthy volunteers. The activities of PON-1 forms, GST-π were determined spectrophotometrically. Concentrations of PON-1, MDA, HNE-adducts, oxLDL, HDL, CH were measured using commercial tests. Results: Near 2-fold higher concentrations of MDA, HNE-adducts, oxLDL, correlating with inflammatory markers in AP patients compared to healthy subjects were demonstrated, which were accompanied by gradually increasing CH/HDL ratio during hospitalization. During hospital treatment, decreased activities of all PON-1 subtypes were observed in AP patients compared to healthy subjects, more pronounced in tobacco smokers. A decreased PON-1 phosphotriesterase activity in non-AP control group smokers compared to non-smokers was noted. In non-smoking AP patients GST-π activity normalized during hospitalization in contrast to smokers. Conclusions: GST-π and PON-1 phosphotriesterase activities seem to be a sensitive marker of pro/antioxidative imbalance in smokers. Lipids peroxidation products generated during AP can intensify preexisting inflammation. Increasing stay in the hospital was associated with worsening of lipids peroxidation markers and the parameters of lipid profile, in both non-smoking and smoking AP patients, what can indicate that the oxidative-inflammatory process are not extinguished.
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Affiliation(s)
- Grzegorz Marek
- Second Department of General and Oncological Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Milena Ściskalska
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Zygmunt Grzebieniak
- Second Department of General and Oncological Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Halina Milnerowicz
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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Kolber W, Dumnicka P, Maraj M, Kuśnierz-Cabala B, Ceranowicz P, Pędziwiatr M, Maziarz B, Mazur-Laskowska M, Kuźniewski M, Sporek M, Walocha J. Does the Automatic Measurement of Interleukin 6 Allow for Prediction of Complications during the First 48 h of Acute Pancreatitis? Int J Mol Sci 2018; 19:ijms19061820. [PMID: 29925813 PMCID: PMC6032432 DOI: 10.3390/ijms19061820] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/08/2018] [Accepted: 06/17/2018] [Indexed: 12/11/2022] Open
Abstract
Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, which reduces mortality. Serum interleukin-6 (IL-6) has been proposed as a biomarker to assist early diagnosis of SAP, however, most data come from studies utilizing IL-6 measurements with ELISA. Our aim was to verify the diagnostic usefulness of IL-6 for the prediction of SAP, organ failure, and need for intensive care in the course of AP using a fully automated assay. The study included 95 adult patients with AP of various severity (29 mild, 58 moderately-severe, 8 severe) admitted to a hospital within 24 h from the onset of symptoms. Serum IL-6 was measured using electochemiluminescence immunoassay in samples collected on admission and on the next day of hospital stay. On both days, patients with SAP presented the highest IL-6 levels. IL-6 correlated positively with other inflammatory markers (white blood cell and neutrophil counts, C-reactive protein, procalcitonin), the markers of renal injury (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and the markers of endothelial dysfunction (angiopoietin-2, soluble fms-like tyrosine kinase-1). IL-6 on admission significantly predicted SAP, vital organ failure, and the need for intensive care or death, with areas under the receiver operating curve between 0.75 and 0.78, not significantly different from multi-variable prognostic scores. The fully automated assay allows for fast and repeatable measurements of serum IL-6, enabling wider clinical use of this valuable biomarker.
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Affiliation(s)
- Witold Kolber
- Department of Surgery, Complex of Health Care Centers in Wadowice, Karmelicka 5 St., 34-100 Wadowice, Poland.
| | - Paulina Dumnicka
- Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
| | - Małgorzata Maraj
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka 16 St., 31-531 Krakow, Poland.
| | - Beata Kuśnierz-Cabala
- Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15A St., 31-501 Krakow, Poland.
| | - Piotr Ceranowicz
- Department of Physiology, Jagiellonian University Medical College, Grzegorzecka 16 St., 31-531 Krakow, Poland.
| | - Michał Pędziwiatr
- 2nd Department of Surgery, Jagiellonian University Medical College, Kopernika 21 St., 31-501 Krakow, Poland.
| | - Barbara Maziarz
- Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15A St., 31-501 Krakow, Poland.
| | | | - Marek Kuźniewski
- Department of Nephrology, Jagiellonian University Medical College, Kopernika 15 St., 31-501 Krakow, Poland.
| | - Mateusz Sporek
- Department of Anatomy, Jagiellonian University Medical College, Kopernika 12 St., 31-034 Krakow, Poland.
| | - Jerzy Walocha
- Department of Anatomy, Jagiellonian University Medical College, Kopernika 12 St., 31-034 Krakow, Poland.
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Zitinic I, Plavsic I, Poropat G, Hauser G. ERCP induced and non-ERCP-induced acute pancreatitis: Two distinct clinical entities? Med Hypotheses 2018; 113:42-44. [PMID: 29523291 DOI: 10.1016/j.mehy.2018.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Revised: 01/28/2018] [Accepted: 02/18/2018] [Indexed: 12/12/2022]
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disease of varied etiology; however, the most common causes of AP are gallstones and alcohol abuse. AP has emerged as the most frequent complication after endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis is generally a clinically irrelevant condition; however, it can be severe or even fatal in up to 0.8% of cases. Different clinical courses and outcomes have been observed between mild and severe AP of different etiologies (i.e., non-ERCP AP and post-ERCP AP), which opens the discussion as to whether they are the same or distinct clinical entities.
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Affiliation(s)
- Ivana Zitinic
- Centre for Emergency Medicine, Clinical Hospital Centre, Rijeka, Croatia
| | - Ivana Plavsic
- Department of Anesthesiology, Clinical Hospital Centre, Rijeka, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Rijeka, Medical Faculty, University of Rijeka, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Rijeka, Medical Faculty, University of Rijeka, Croatia.
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Meng S, Wang H, Xue D, Zhang W. Screening and validation of differentially expressed extracellular miRNAs in acute pancreatitis. Mol Med Rep 2017; 16:6412-6418. [PMID: 28849189 DOI: 10.3892/mmr.2017.7374] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 06/08/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to screen for differentially expressed extracellular microRNAs (miRNAs) during the development of acute pancreatitis (AP) and validate the miRNA expression in the plasma of patients with AP. The culture medium of taurolithocholic acid‑3 sulfate‑treated rat pancreatic acinar AR42J cells was collected to extract total RNA for miRNA microarray analysis. Compared with the miRNA test results of the AP rats in the GEO databases, the differentially expressed extracellular miRNAs were screened. The TargetScan, miRanda, and PicTar programs were used for target gene prediction of the identified miRNAs, and gene ontology‑biological processes (GO‑BP) functional annotation was performed. Finally, the results from the combined microarray analyses (in vitro cell line and in vivo rat samples) were validated using plasma samples from patients with mild and moderately severe AP by reverse transcription‑polymerase chain reaction. The results demonstrated that extracellular miR‑24 was differentially expressed by microarray and bioinformatics analysis in both the cell line and the animal model of AP. Bioinformatics prediction analysis revealed that downstream target genes of miR‑24 included Vav2, Syk, Lhcgr, Slc9a3r1, Cacnb1, Cacna1b, Bcl10, and Fgd3. Functional enrichment analysis revealed that the main GO‑BP predicted functional presentations were positive regulation of calcium‑mediated signaling, activation of c‑Jun N‑terminal kinase activity, calcium ion transport, regulation of Rho protein signal transduction, negative regulation of the protein kinase B signaling cascade, and the T cell receptor signaling pathway. Validation analysis for the plasma miR‑24 expression in humans revealed a significant upregulation of miR‑24 in the plasma samples of AP patients compared with the healthy controls, while no significant difference was observed in the miR‑24 expression between the mild and the moderately severe AP groups. The present study confirmed the high expression of miR‑24 in peripheral blood during AP, suggesting that miR‑24 might have an intercellular communication role contributing to the AP‑associated distant organ injury.
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Affiliation(s)
- Shishuai Meng
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Hao Wang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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NAD + augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling. Sci Rep 2017; 7:3006. [PMID: 28592850 PMCID: PMC5462749 DOI: 10.1038/s41598-017-03418-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 04/27/2017] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD+) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD+ levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD+ levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD+ levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD+ by NQO1 enzymatic action using the substrate β-Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP.
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Effects of Tocilizumab on Experimental Severe Acute Pancreatitis and Associated Acute Lung Injury. Crit Care Med 2017; 44:e664-77. [PMID: 26963319 DOI: 10.1097/ccm.0000000000001639] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To examine the therapeutic effects of tocilizumab, an antibody against interleukin-6 receptor, on experimental severe acute pancreatitis and associated acute lung injury. The optimal dose of tocilizumab and the activation of interleukin-6 inflammatory signaling were also investigated. DESIGN Randomized experiment. SETTING Research laboratory at a university hospital. SUBJECT Experimental severe acute pancreatitis in rats. INTERVENTIONS Severe acute pancreatitis was induced by retrograde injection of sodium taurocholate (50 mg/kg) into the biliopancreatic duct. In dose-study, rats were administered with different doses of tocilizumab (1, 2, 4, 8, and 16 mg/kg) through the tail vein after severe acute pancreatitis induction. In safety-study, rats without severe acute pancreatitis induction were treated with high doses of tocilizumab (8, 16, 32, and 64 mg/kg). Serum and tissue samples of rats in time-study were collected for biomolecular and histologic evaluations at different time points (2, 6, 12, 18, and 24 hr). MEASUREMENTS AND MAIN RESULTS 1) Under the administration of tocilizumab, histopathological scores of pancreas and lung were decreased, and severity parameters related to severe acute pancreatitis and associated lung injury, including serum amylase, C-reactive protein, lung surfactant protein level, and myeloperoxidase activity, were all significant alleviated in rat models. 2) Dose-study demonstrated that 2 mg/kg tocilizumab was the optimal treatment dose. 3) Basing on multi-organ pathologic evaluation, physiological and biochemical data, no adverse effect and toxicity of tocilizumab were observed in safety-study. 4) Pancreatic nuclear factor-κB and signal transducer and activator of transcription 3 were deactivated, and the serum chemokine (C-X-C motif) ligand 1 was down-regulated after tocilizumab administration. CONCLUSIONS Our study demonstrated tocilizumab, as a marketed drug commonly used for immune-mediated diseases, was safe and effective for the treatment of experimental severe acute pancreatitis and associated acute lung injury. Our findings provide experimental evidences for potential clinical application of tocilizumab in severe acute pancreatitis and associated complications.
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Dumnicka P, Maduzia D, Ceranowicz P, Olszanecki R, Drożdż R, Kuśnierz-Cabala B. The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications. Int J Mol Sci 2017; 18:E354. [PMID: 28208708 PMCID: PMC5343889 DOI: 10.3390/ijms18020354] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/17/2017] [Accepted: 01/31/2017] [Indexed: 02/07/2023] Open
Abstract
Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients.
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Affiliation(s)
- Paulina Dumnicka
- Department of Medical Diagnostics, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
| | - Dawid Maduzia
- Department of Anatomy, Jagiellonian University Medical College, Kopernika 12, 31-034 Kraków, Poland.
| | - Piotr Ceranowicz
- Department of Physiology, Jagiellonian University Medical College, Grzegórzecka 16, 31-531 Kraków, Poland.
| | - Rafał Olszanecki
- Department of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, 31-531 Kraków, Poland.
| | - Ryszard Drożdż
- Department of Medical Diagnostics, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
| | - Beata Kuśnierz-Cabala
- Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15A, 31-501 Kraków, Poland.
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Abstract
Acute pancreatitis is a common disease that can progress to gland necrosis, which imposes significant risk of morbidity and mortality. In general, the treatment for pancreatitis is a supportive therapy. However, there are several reasons to escalate to surgery or another intervention. This review discusses the pathophysiology as well as medical and interventional management of necrotizing pancreatitis. Current evidence suggests that patients are best served by delaying interventions for at least 4 weeks, draining as a first resort, and debriding recalcitrant tissue using minimally invasive techniques to promote or enhance postoperative recovery while reducing wound-related complications.
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Fu Q, Qin T, Chen L, Liu CJ, Zhang X, Wang YZ, Hu MX, Chu HY, Zhang HW. miR-29a up-regulation in AR42J cells contributes to apoptosis via targeting TNFRSF1A gene. World J Gastroenterol 2016; 22:4881-4890. [PMID: 27239114 PMCID: PMC4873880 DOI: 10.3748/wjg.v22.i20.4881] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 02/29/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of miR-29a in rat acute pancreatitis and its functional role in AR42J cell apoptosis.
METHODS: Twelve SD rats were divided into a control group and an acute edematous pancreatitis (AEP) group randomly. AEP was induced by intraperitoneal injection of L-arginine (150 mg/kg) in the AEP group and equal volume of 0.9% NaCl was injected in the control group. The apoptosis of acinar cells in pancreatic tissue was determined by TUNEL assay. miRNA chip assay was performed to examine the expression of miRNAs in two groups. Besides, to further explore the role of miR-29a in apoptosis in vitro, recombinant rat TNF-α (50 ng/mL) was administered to treat the rat pancreatic acinar cell line AR42J for inducing AR42J cell apoptosis. Quantitative real-time PCR (qRT-PCR) was adopted to measure miR-29a expression. Then, miRNA mimic, miRNA antisense oligonucleotide (AMO) and control vector were used to transfect AR42J cells. The expression of miR-29a was confirmed by qRT-PCR and the apoptosis rate of AR42J cells was detected by flow cytometry analysis. Western blot was used to detect the expression of activated caspase3. Moreover, we used bioinformatics software and luciferase assay to test whether TNFRSF1A was the target gene of miR-29a. After transfection, qRT-PCR and Western blot was used to detect the expression of TNFRSF1A in AR42J cells after transfection.
RESULTS: The expression of miR-29a was much higher in the AEP group compared with the control group as displayed by the miRNA chip assay. After inducing apoptosis of AR42J cells in vitro, the expression of miR-29a was significantly increased by 1.49 ± 0.04 times in comparison with the control group. As revealed by qRT-PCR assay, the expression of miR-29a was 2.68 ± 0.56 times higher in the miR-29a mimic group relative to the control vector group, accompanied with an obviously increased acinar cell apoptosis rate (42.83 ± 1.25 vs 24.97 ± 0.15, P < 0.05). Moreover, the expression of miR-29a in the miRNA AMO group was 0.46 ± 0.05 times lower than the control vector group, and the cell apoptosis rate was much lower accordingly (17.27 ± 1.36 vs 24.97 ± 0.15, P < 0.05). The results of bioinformatics software and luciferase assay showed that TNFRSF1A might be a target gene of miR-29a. TNFRSF1A expression was up-regulated in the miR-29a mimic group, while the miR-29a AMO group showed the reverse trend.
CONCLUSION: miR-29a might promote the apoptosis of AR42J cells via up-regulating the expression of its target gene TNFRSF1A.
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DENG YUANYUAN, SHAMOON MUHAMMAD, HE YUE, BHATIA MADHAV, SUN JIA. Cathelicidin-related antimicrobial peptide modulates the severity of acute pancreatitis in mice. Mol Med Rep 2016; 13:3881-3885. [PMID: 27035328 PMCID: PMC4838156 DOI: 10.3892/mmr.2016.5008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
The present study aimed to investigate the immunomodulatory effects of mouse cathelicidin-related antimicrobial peptide (CRAMP) on experimental acute pancreatitis (AP). AP is a common clinical condition characterized by acute abdominal inflammation. Innate immune cells and mediators are intrinsically linked to the pathogenesis of AP. Cathelicidins are innate immunity-derived antimicrobial peptides that exert immunomodulatory effects on various host cells. However, how cathelicidins are involved and modulate the severity and inflammatory responses of AP remains unclear. In the present study, the mouse CRAMP gene‑deficient cnlp‑/‑ mice and their wild‑type C57BL/6J littermates were induced with AP by multiple hourly injections of supramaximal doses of caerulein. Serum amylase levels, pancreatic myeloperoxidase activity and histological examination were performed in order to determine the disease severity and the levels of inflammatory cytokines. Disease severity and inflammatory markers were subsequently evaluated in the control mice, cnlp‑/‑ C57BL/6J mice with AP, and wild‑type C57BL/6J mice with AP. The results demonstrated that cnlp‑/‑ mice exhibited a more severe phenotype and inflammatory response following AP induction compared with the wild‑type mice, as evidenced by increased serum amylase levels, pancreatic myeloperoxidase release, and early inflammatory mediator tumor necrosis factor‑α production. Histological examination confirmed that CRAMP deficiency worsened the pancreatic inflammatory condition. These results indicate that CRAMP may be considered a novel modulatory mediator in mouse experimental AP.
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Affiliation(s)
- YUAN-YUAN DENG
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - MUHAMMAD SHAMOON
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - YUE HE
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - MADHAV BHATIA
- Department of Pathology, University of Otago, Christchurch 8140, New Zealand
| | - JIA SUN
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
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Liang X, Zhang B, Chen Q, Zhang J, Lei B, Li B, Wei Y, Zhai R, Liang Z, He S, Tang B. The mechanism underlying alpinetin-mediated alleviation of pancreatitis-associated lung injury through upregulating aquaporin-1. Drug Des Devel Ther 2016; 10:841-50. [PMID: 26966354 PMCID: PMC4771394 DOI: 10.2147/dddt.s97614] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Characterized by its acute onset, critical condition, poor prognosis, and high mortality rate, severe acute pancreatitis (SAP) can cause multiple organ failure at its early stage, particularly acute lung injury (ALI). The pathogenesis of ALI is diffuse alveolar damage, including an increase in pulmonary microvascular permeability, a decrease in compliance, and invasion of many inflammatory cells. Corticosteroids are the main treatment method for ALI; however, the associated high toxicity and side effects induce pain in patients. Recent studies show that the effective components in many traditional Chinese medicines can effectively inhibit inflammation with few side effects, which can decrease the complications caused by steroid consumption. Based on these observations, the main objective of the current study is to investigate the effect of alpinetin, which is a flavonoid extracted from Alpinia katsumadai Hayata, on treating lung injury induced by SAP and to explore the mechanism underlying the alpinetin-mediated decrease in the extent of ALI. In this study, we have shown through in vitro experiments that a therapeutic dose of alpinetin can promote human pulmonary microvascular endothelial cell proliferation. We have also shown via in vitro and in vivo experiments that alpinetin upregulates aquaporin-1 and, thereby, inhibits tumor necrosis factor-α expression as well as reduces the degree of lung injury. Overall, our study shows that alpinetin alleviates SAP-induced ALI. The likely molecular mechanism includes upregulated aquaporin expression, which inhibits tumor necrosis factor-α and, thus, alleviates SAP-induced ALI.
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Affiliation(s)
- Xingsi Liang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Infectious Diseases, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Bin Zhang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China
| | - Quan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, People's Republic of China
| | - Jing Zhang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Biao Lei
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Bo Li
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Yangchao Wei
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Run Zhai
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Zhiqing Liang
- Department of Infectious Diseases, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Songqing He
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
| | - Bo Tang
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China; Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China
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Inflammation and Inflammatory Diseases, Markers, and Mediators: Role of CRP in Some Inflammatory Diseases. BIOLOGY OF C REACTIVE PROTEIN IN HEALTH AND DISEASE 2016. [PMCID: PMC7122703 DOI: 10.1007/978-81-322-2680-2_4] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Sun FL, Li HP, Teng YS, Shang D. Therapeutic effects of rat bone marrow-derived mesenchymal stem cells combined with Dachengqi decoction in rats with severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2015; 23:4167-4176. [DOI: 10.11569/wcjd.v23.i26.4167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the therapeutic effects of mesenchymal stem cells (MSCs) combined with Dachengqi decoction (DcqD) in rats with severe acute pancreatitis (SAP) and to explore the underlying mechanism.
METHODS: Sixty male Sprague-Dawley rats were randomly divided into sham-operated (SO), model-control (MC), MSCs-treatment (1.0 × 106 MSCs; MSC group), DcqD-treatment (1 mL/100 g; DD group), and MSCs-plus-DcqD-treatment (MSCDD group) groups (n = 12). SAP was induced in rats by retrograde infusion of 1.5% sodium deoxycholate into the biliopancreatic duct. Isolation and culture of MSCs were performed by Percoll density gradient centrifugation and plastic adherence separating. Ahead of infusion, MSCs were labelled with DAPI via the tail vein. After 24 h of administration, distribution of MSCS in vivo was observed by fluorescence microscopy. Neutrophil apoptosis was identified by flow cytometry. Serum levels of amylase, lipase, tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10 and blood CD4+CD25+ regulatory T cells (CD4+CD25+Tregs) percentages were determined. Mortality, pathological changes in the pancreas, and histological scores were assessed.
RESULTS: The mortality rate of SAP rats was significantly lower in the treatment groups. Under a fluorescence microscope, the lumen tissue in the pancreatic sections of the MSC group exhibited bright blue fluorescence, whereas that in the MC group did not. Compared with the MC group, the MSC, DD and MSCDD groups had a significant decrease in TNF-α, IL-6, amylase, and lipase (P < 0.05). IL-10 and CD4+CD25+Tregs percentage were significantly higher in the MSCDD group than in the SAP, MSC and DD groups. However, there was no significant difference between the MSCDD and SO groups in IL-10 or CD4+CD25+Tregs percentage (P > 0.05). The pancreatic pathological changes and histopathologic scores were attenuated in the treatment groups, especially in the MSCDD group.
CONCLUSION: The combined therapy proved to be more effective than either MSC or DD alone and may cause synergistic effects in the early stage of SAP. The potential mechanisms that might account for the favourable effects include participating in injured pancreas repair, switching from neutrophils or acinar cell necrosis to apoptosis and inhibiting over-inflammatory reaction.
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