Galangin ameliorates severe acute pancreatitis in mice by activating the nuclear factor E2-related factor 2/heme oxygenase 1 pathway.

Acute pancreatitis (AP) is a common serious acute condition of the digestive system that remains a clinical challenge. Severe acute pancreatitis (SAP) in particular is characterized by high morbidity and mortality. The present study was designed to investigate the protective effect of Galangin (Gal), a natural flavonol obtained from lesser galangal, on L-arginine-induced SAP in mice and in AR42J cells. Amylase and lipase activities were measured and the histopathology of the pancreas, lung, and kidney was evaluated. Inflammation and oxidative stress were assessed using ELISA, western blotting, RT-PCR, and immunohistochemistry. Gal was shown to reduce proinflammatory cytokine production and reactive oxygen species (ROS) generation in vivo and in vitro. L-arginine treatment reduced the expression of components of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and the downstream protein heme oxygenase-1 (HO-1) in mice, whereas Gal increased their expression. Furthermore, the Nrf2/HO-1 pathway inhibitor brusatol prevented the anti-inflammatory and antioxidant effects of Gal in mice with SAP. Taken together, our results imply that Gal has protective effects in L-arginine-induced SAP that are induced by the upregulation of the Nrf2/HO-1 pathway, which has anti-inflammatory and antioxidant effects. Thus, Gal may represent a promising treatment for SAP.

Prevalence of imaging findings of acute pancreatitis in emergency department patients with elevated serum lipase.

PURPOSE: To assess the association of imaging features of acute pancreatitis (AP) with the magnitude of lipase elevation in Emergency Department (ED) patients. METHODS: This Institutional Review Board-approved retrospective study included 509 consecutive patients presenting from 9/1/13-8/31/15 to a large academic ED with serum lipase levels ≥3× the upper limit of normal (ULN) (≥180 U/L). Patients were excluded if they did not have imaging (n = 131) or had a history of trauma, abdominal metastases, altered mental status, or transfer from an outside hospital (n = 190); the final study population was 188 patients. Imaging exams were retrospectively evaluated, and a consensus opinion of two subspecialty-trained abdominal radiologists was used to diagnose AP. Primary outcome was presence of imaging features of AP stratified by lipase level (≥3×-10× ULN and > 10× ULN). Secondary outcome was rate of discordant consensus evaluation compared to original radiologist's report. RESULTS: 25.0% of patients (47/188) had imaging features of AP. When lipase was >10× ULN (n = 94), patients were more likely to have imaging features of AP (34%) vs. those with mild elevation (16%) (p = 0.0042). There was moderately strong correlation between lipase level and presence of imaging features of AP (r = 0.48, p < 0.0001). Consensus review of CT and MRI images was discordant with the original report in 14.9% (28/188) of cases. CONCLUSION: Prevalence of imaging signs of AP in an ED population with lipase ≥3× ULN undergoing imaging is low. However, the probability of imaging features of AP increases as lipase value increases.

Sulfiredoxin-1 attenuates injury and inflammation in acute pancreatitis through the ROS/ER stress/Cathepsin B axis.

Acinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.

Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1.

Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.

Low Frequency of Acute Pancreatitis in Hospitalized COVID-19 Patients.

OBJECTIVE: The clinical significance of increased serum pancreatic enzymes (PEs) in coronavirus disease 2019 (COVID-19) patients has not yet been fully understood. We aimed to investigate the frequency and the impact on clinical outcome of PE elevation and acute pancreatitis in such patients. METHODS: Clinical data, laboratory tests, and cross-sectional images were analyzed from COVID-19 patients admitted to the Tor Vergata Hospital in Rome. Variables associated with PE abnormalities, intensive care unit (ICU) admission, or death were investigated through univariate and multivariate analyses and Cox proportional hazard model. RESULTS: Pancreatic enzymes were available in 254 of 282 COVID-19 patients. Among these, 66 patients (26%) showed mild elevation of PE, and 11 patients (4.3%) had severe elevation (>3 times of the upper limit of normal). Overall, 2 patients met the diagnostic criteria for acute pancreatitis. Hepatic and renal involvements were associated with PE elevation. Multivariate analysis showed that mild and severe PE elevations were significantly associated with ICU admission (odds ratios, 5.51 [95% confidence interval, 2.36-12.89; P < 0.0001] and 26.2 [95% confidence interval, 4.82-142.39; P < 0.0001]). CONCLUSIONS: Increase in serum PE, but not acute pancreatitis, is frequent in hospitalized COVID-19 patients and associates with ICU admission.

Hyperlipasemia in absence of acute pancreatitis is associated with elevated D-dimer and adverse outcomes in COVID 19 disease.

BACKGROUND: Coronavirus SARS-CoV-2 affects multiple organs. Studies have reported mild elevations of lipase levels of unclear significance. Our study aims to determine the outcomes in patients with COVID-19 and hyperlipasemia, and whether correlation with D-dimer levels explains the effect on outcomes. METHODS: Case-control study from two large tertiary care health systems, of patients with COVID-19 disease admitted between March 1 and May 1, 2020 who had lipase levels recorded. Data analyzed to study primary outcomes of mortality, length of stay (LOS) and intensive care utilization in hyperlipasemia patients, and correlation with D-dimer and outcomes. RESULTS: 992 out of 5597 COVID-19 patients had lipase levels, of which 429 (43%) had hyperlipasemia. 152 (15%) patients had a lipase > 3x ULN, with clinical pancreatitis in 2 patients. Hyperlipasemia had a higher mortality than normal lipase patients (32% vs. 23%, OR = 1.6,95%CI = 1.2-2.1, P = 0.002). In subgroup analysis, hyperlipasemia patients had significantly worse LOS (11vs.15 days, P = 0.01), ICU admission rates (44% vs. 66%,OR = 2.5,95%CI = 1.3-5.0,P = 0.008), ICU LOS (12vs.19 days,P = 0.01), mechanical ventilation rates (34% vs. 55%,OR = 2.4,95%CI = 1.3-4.8,P = 0.01), and durations of mechanical ventilation (14 vs. 21 days, P = 0.008). Hyperlipasemia patients were more likely to have a D-dimer value in the highest two quartiles, and had increased mortality (59% vs. 15%,OR = 7.2,95%CI = 4.5-11,P < 0.001) and LOS (10vs.7 days,P < 0.001) compared to those with normal lipase and lower D-dimer levels. CONCLUSION: There is high prevalence of hyperlipasemia without clinical pancreatitis in COVID-19 disease. Hyperlipasemia was associated with higher mortality and ICU utilization, possibly explained by elevated D-dimer.

Resveratrol Suppresses Severe Acute Pancreatitis-Induced Microcirculation Disturbance through Targeting SIRT1-FOXO1 Axis.

BACKGROUND: Resveratrol (RSV), one of the SIRT1 agonists, has the ability of alleviating severe acute pancreatitis (SAP); however, the concrete protective mechanism remains unknown. It is noteworthy that microcirculation disturbance plays a vital role in SAP, and the SIRT1/FOX1 axis can regulate microcirculation. Therefore, this study is aimed at ascertaining what is the underlying mechanism of the protective effect of RSV on SAP, and whether it is associated with alleviating microcirculation disturbance by regulating the SIRT1/FOX1 axis. METHOD: The model of SAP was induced by retrograde injection of sodium taurodeoxycholate into the bile duct of the rats. The pancreatic wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α ratios; microcirculatory function; and SIRT1 activity were examined. ELISA was used to examine the serum level of lipase, amylase, hemorheology, ET, NO, TXB2, and 6-keto-PGF1α and the content of SIRT1, VEGF, Ang I, and Ang II in the pancreas. RT-PCR was used to examine the mRNA level of VEGF, Ang I, and Ang II. Western blotting was used to detect SIRT1, FOXO1, and acetyl-FOXO1. Immunoprecipitation was used to examine the interaction of SIRT1 and FOXO1. RESULTS: Resveratrol can significantly decrease the expression of lipase, amylase, acetyl-FOXO1, VEGF, Ang II, ET, NO, TXB2, and 6-keto-PGF1α and the ratio of wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α by improving microcirculatory dysfunction and blood viscosity in SAP. Moreover, resveratrol can also promote the interaction of SIRT1 and FOXO1 and increase SIRT1 activity and the expression of SIRT1 and Ang I. The SIRT1 inhibitor, Sirtinol (EX527), obliviously reversed the effects of RSV on SAP. CONCLUSION: Resveratrol can protect rats against SAP, and its protective mechanism is associated with suppressing microcirculation disturbance through activating SIRT1-FOXO1 axis.

Wip1 Aggravates the Cerulein-Induced Cell Autophagy and Inflammatory Injury by Targeting STING/TBK1/IRF3 in Acute Pancreatitis.

Acute pancreatitis (AP) is an inflammatory reaction of pancreatic tissue self-digestion, edema, hemorrhage, and even necrosis after the activation of pancreatic enzymes in the pancreas caused by a variety of etiologies. This study was aimed to explore the functions and mechanism of Wip1 in AP. Twenty male SD rats were randomly assigned into 2 groups (control group: saline treatment; AP group: cerulein treatment). And cerulein-treated AR42J cells were conducted as AP model in vitro. The levels of amylase were detected by using the Beckman biochemical analyzer. The levels of IFNß and TNFα were analyzed by ELISA. The autophagosomes were observed by transmission electron microscopy. The Wip1-specific shRNAs were transfected to AR42J cells to silence the expression of Wip1. The levels of Wip1 were measured by qRT-PCR and Western blot. The levels of STING/TBK1/IRF3 and LC3 were measured by Western blot. The AP model was successfully constructed by cerulein administration. Wip1 was notably upregulated in AP models. Autophagy and STING pathway activation were involved in the development of AP. Wip1 inhibition counteracts the promotion effect on inflammatory response induced by cerulein in AR42J Cells. Wip1 inhibition inhibited the activity of the STING/TBK1/IRF3 and reduced LC3 levels in AP. This study preliminarily explored that Wip1 could regulate autophagy and participate in the development of AP through the STING/TBK1/IRF3 signaling pathway.

Involvement of the exocrine pancreas during COVID-19 infection and possible pathogenetic hypothesis: a concise review.

The gastrointestinal system may be affected by COVID-19 infection with an incidence variable from 3% up to 79%. Several works show that the pancreas, both in its exocrine and endocrine function, can be affected by this viral infection, although this organ has been poorly analyzed in this current epidemic context. This mini-review aims to provide a summary of available studies on exocrine pancreas involvement during COVID-19 infection. A search through MEDLINE/PubMed was conducted on the topic in hand. With regard to exocrine function, some studies highlight the presence of an associated hyperenzymemia (hyperamylasemia, hyperlipasemia), while others describe isolated and rare cases of acute pancreatitis. More attention should be paid to pancreatic impairment in subjects with COVID-19, as this may prove to be one of the elements aggravating its clinical course. Indeed, acute pancreatitis, especially when presenting in severe forms with hyperstimulation of the pro-inflammatory response, may represent a crucial factor in the progression of COVID-19, entailing both an increase in hospitalization days and in mortality rate.

Inhibition of CHRM3 Alleviates Necrosis Via the MAPK-p38/miR-31-5p/RIP3 Axis in L-Arginine-Induced Severe Acute Pancreatitis.

OBJECTIVES: Pancreatic acinar necrosis is a typical feature in the early phase of severe acute pancreatitis (SAP). Muscarinic acetylcholine receptor M3 (CHRM3) has been reported to play important roles in promoting insulin secretion and tumor cell proliferation, but its effect on necrosis remains unknown. This study revealed the important role of CHRM3 in regulating L-arginine-induced SAP and the molecular mechanisms. METHODS: To verify the function of CHRM3, pancreatic tissues and primary acinar cells of CRISPR/Cas9-mediated Chrm3 knockout mice were used in CHRM3 knockdown experiments, and to ascertain the CHRM3 overexpression, PLV-EGFP-Chrm3 plasmids were transfected in acinar cells in vitro. RESULTS: In L-arginine-induced SAP, CHRM3 is activated and regulates SAP through the mitogen-activated protein kinase/p38 pathway. Moreover, the expression of miR-31-5p decreased in the SAP model both in vitro and in vivo. Mir-31-5p effects the necrosis of acinar cells in SAP by upregulating the target gene RIP3, and miR-31-5p is a downstream miRNA of CHRM3. CONCLUSIONS: Necrosis in L-arginine-induced SAP is promoted by CHRM3 through the mitogen-activated protein kinase-p38/miR-31-5p/RIP3 axis.

A Paper-Based Near-Infrared Optical Biosensor for Quantitative Detection of Protease Activity Using Peptide-Encapsulated SWCNTs.

A protease is an enzyme that catalyzes proteolysis of proteins into smaller polypeptides or single amino acids. As crucial elements in many biological processes, proteases have been shown to be informative biomarkers for several pathological conditions in humans, animals, and plants. Therefore, fast, reliable, and cost-effective protease biosensors suitable for point-of-care (POC) sensing may aid in diagnostics, treatment, and drug discovery for various diseases. This work presents an affordable and simple paper-based dipstick biosensor that utilizes peptide-encapsulated single-wall carbon nanotubes (SWCNTs) for protease detection. Upon enzymatic digestion of the peptide, a significant drop in the photoluminescence (PL) of the SWCNTs was detected. As the emitted PL is in the near-infrared region, the developed biosensor has a good signal to noise ratio in biological fluids. One of the diseases associated with abnormal protease activity is pancreatitis. In acute pancreatitis, trypsin concentration could reach up to 84 µg/mL in the urine. For proof of concept, we demonstrate the feasibility of the proposed biosensor for the detection of the abnormal levels of trypsin activity in urine samples.

The role of asparagine synthetase on nutrient metabolism in pancreatic disease.

The pancreas avidly takes up and synthesizes the amino acid asparagine (Asn), in part, to maintain an active translational machinery that requires incorporation of the amino acid. The de novo synthesis of Asn in the pancreas occurs through the enzyme asparagine synthetase (ASNS). The pancreas has the highest expression of ASNS of any organ, and it can further upregulate ASNS expression in the setting of amino acid depletion. ASNS expression is driven by an intricate feedback network within the integrated stress response (ISR), which includes the amino acid response (AAR) and the unfolded protein response (UPR). Asparaginase is a cancer chemotherapeutic drug that depletes plasma Asn. However, asparaginase-associated pancreatitis (AAP) is a major medical problem and could be related to pancreatic Asn depletion. In this review, we will provide an overview of ASNS and then describe its role in pancreatic health and in the exocrine disorders of pancreatitis and pancreatic cancer. We will offer the overarching perspective that a high abundance of ASNS expression is hardwired in the exocrine pancreas to buffer the high demands of Asn for pancreatic digestive enzyme protein synthesis, that perturbations in the ability to express or upregulate ASNS could tip the balance towards pancreatitis, and that pancreatic cancers exploit ASNS to gain a metabolic survival advantage.

Quantification analysis of lactate dehydrogenase and C-reactive protein in evaluation of the severity and prognosis of the acute pancreatitis.

To evaluate the value of C-reactive protein (CRP) and lactate dehydrogenase (LDH) in assessing the severity and prognosis of acute pancreatitis (AP). A retrospective analysis was performed with the clinical data of 115 AP patients who were delivered to this hospital between December 2012 and December 2017 for treatment, in which there were 76 patients with mild AP (MAP group) and 39 with moderately severe AP (MSAP) and severe AP (SAP) (non-MAP group). Within 24 h after admission, we detected the levels of CRP, LDH and amylase (AMY) in serum, and according to the sensitivity and specificity of CRP, LDH and AMY, as well as the SROC curve, we evaluated the diagnostic value of these indicators in assessing the severity of AP. In serum, the levels of CRP and LDH in the non-MAP group were significantly higher than those in the MAP group (P <0.05). And in predicting the development of AP, the sensitivity, specificity and accordance rate of CRP were 59.0%, 97.4% and 84.3%, with a cut-off value of 176.00 mg/L; for LDH, these indexes were 94.9%, 88.2% and 90.4%, with a cut-off value of 235.50 U/L. Thus, LDH, combined with the CRP can well predict the incidence rate of the MODS and mortality rate of AP. Finally, we conclude that within 24 h after admission, the levels of CRP and LDH in patients can serve as indicators for evaluating the severity and prognosis of AP.

Histopathological findings and canine pancreatic lipase immunoreactivity in normal dogs and dogs with inflammatory and neoplastic diseases of the pancreas.

BACKGROUND: Diagnosis of pancreatic diseases in dogs is still challenging because of variable clinical signs, which do not always correspond with clinical pathology and histopathological findings. OBJECTIVES: To characterize inflammatory and neoplastic pancreatic diseases of dogs and to correlate these findings with clinical findings and canine pancreatic lipase immunoreactivity (cPLI) results. ANIMALS: Tissue specimens and corresponding blood samples from 72 dogs submitted for routine diagnostic testing. METHODS: Four groups were defined histologically: (1) normal pancreas (n = 40), (2) mild pancreatitis (n = 8), (3) moderate or severe pancreatitis (acute, n = 11; chronic, n = 1), and (4) pancreatic neoplasms (n = 12). An in-house cPLI ELISA (<180 µg/L, normal; >310 µg/L, pancreatitis) was performed. RESULTS: In dogs with normal pancreas, 92.5% of serum cPLI results were within the reference range and significantly lower than in dogs with mild acute pancreatitis, moderate or severe acute pancreatitis and pancreatic tumors. In dogs with moderate or severe acute pancreatitis, cPLI sensitivity was 90.9% (95% confidence interval [CI], 58.7%-99.8%). Most dogs (9/12) with pancreatic tumors (group 4) had additional pancreatic inflammation and cPLI results were increased in 10 dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: High cPLI indicates serious acute pancreatitis but underlying pancreatic neoplasms should also be taken into consideration. This study confirms the relevance of histopathology in the diagnostic evaluation of pancreatic diseases.

Retrospective study of the diagnostic utility of Spec fPLin the assessment of 274 sick cats.

BACKGROUND: Serum feline pancreatic lipase immunoreactivity (fPL) commonly is used in the assessment of sick cats suspected to have pancreatitis but its diagnostic utility is debated. OBJECTIVES: To evaluate the diagnostic utility of the Spec fPL test and selected serum biochemistry tests in the diagnosis of pancreatitis in cats. ANIMALS: Two hundred seventy-four client-owned cats presented to a university teaching hospital in the United Kingdom, from April 2013 to May 2017, in which Spec fPL was measured. METHODS: Cats were classified into 1 of 4 groups based on clinical signs (all cats), ultrasonographic findings (all cats) and histopathological or cytological assessment of the pancreas where available (9 cats) regardless of Spec fPL concentration. The groups were (a) definite pancreatitis (n = 9), (b) probable pancreatitis (n = 49), (c) possible pancreatitis (n = 139), and (d) unlikely pancreatitis (n = 77). Spec fPL and selected serum biochemistry test results were compared among groups. RESULTS: Serum fPL concentrations >5.3 µg/L were classified as positive and concentrations <3.5 µg/L were classified as negative. There was a significantly (P = .03) lower proportion of false-positive results (cats unlikely to have pancreatitis, n = 77, with a positive fPL, n = 8, 10%) than false-negative results (cats with definite or probable pancreatitis, n = 58, with a negative fPL result, n = 14, 24%). None of the selected biochemical tests were helpful diagnostically. CONCLUSION AND CLINICAL IMPORTANCE: A positive Spec fPL result indicates that pancreatitis is a probable diagnosis, but the test cannot be used to rule the diagnosis out.

Roles of Autophagy and Pancreatic Secretory Trypsin Inhibitor in Trypsinogen Activation in Acute Pancreatitis.

The focus of the review is on roles of autophagy and pancreatic secretory trypsin inhibitor (PSTI), an endogenous trypsin inhibitor, in trypsinogen activation in acute pancreatitis. Acute pancreatitis is a disease in which tissues in and around the pancreas are autodigested by pancreatic digestive enzymes. This reaction is triggered by the intrapancreatic activation of trypsinogen. Autophagy causes trypsinogen and cathepsin B, a trypsinogen activator, to colocalize within the autolysosomes. Consequently, if the resultant trypsin activity exceeds the inhibitory activity of PSTI, the pancreatic digestive enzymes are activated, and they cause autodigestion of the acinar cells. Thus, autophagy and PSTI play important roles in the development and suppression of acute pancreatitis, respectively.

An intact C-terminal end of albumin is required for its long half-life in humans.

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics.

Heparanase in Acute Pancreatitis.

Acute pancreatitis (AP) is one of the most common diseases in gastroenterology, affecting 2% of all hospitalized patients. Nevertheless, neither the etiology nor the pathophysiology of the disease is fully characterized, and no specific or effective treatment has been developed. Heparanase (Hpa) is an endoglycosidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs) into shorter oligosaccharides, activity that is highly implicated in cell invasion associated with cancer metastasis and inflammation. Given that AP is a typical inflammatory disease, we investigated whether Hpa plays a role in AP. Our results provide keen evidence that Hpa expression and activity are significantly increased following cerulein-induced AP in wild type mice. In parallel to the classic manifestations of AP, namely elevation of amylase and lipase levels, pancreas edema and inflammation as well as induction of cytokines and signaling molecules, have been detected in this experimental model of the disease. Noteworthy, these features were far more profound in transgenic mice overexpressing heparanase (Hpa-Tg), suggesting that these mice can be utilized as a model system to reveal the molecular mechanism by which Hpa functions in AP. Further support for the involvement of Hpa in the pathogenesis of AP emerged from our observation that treatment of experimental AP with PG545 or SST0001(= Ronepastat), two potent Hpa inhibitors, markedly attenuated the biochemical, histological and immunological manifestations of the disease. Hpa, therefore, emerges as a potential new target in AP, and Hpa inhibitors are hoped to prove beneficial in AP along with their promising efficacy as anti-cancer compounds.

CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis.

Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. The present study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 µg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 overexpression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 overexpression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.