Vitamin B6 ameliorates acute pancreatitis by suppressing the caspase3 signaling pathway.

BACKGROUND: Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas characterized by pancreatic inflammation and injury to acinar cells. Vitamin B6 (VB6) is a vital nutrient that plays a significant role in preserving human health and has anti-inflammatory and anti-apoptotic effects. METHODS: This study aimed to explore the potential pancreatic protective effects of VB6 in mitigating pancreatic inflammation and apoptosis induced by taurocholate sodium (TLCS) in an AP model and to assess the underlying mechanism of action. AP was induced in Sprague‒Dawley (SD) rats through TLCS administration and lipopolysaccharide (LPS)-treated AR42J cells, followed by treatment with VB6. RESULTS: Various parameters associated with AP were assessed in both plasma and pancreatic tissues. VB6 has been shown to ameliorate the severity of AP through various mechanisms. It effectively reduces the levels of serum amylase, lipase, and inflammatory factors, thereby mitigating histological injury to the pancreas. Moreover, VB6 inhibited pancreatic apoptosis by downregulating bax expression and up-regulating Bcl2 expression in TLCS-treated rats. Additionally, VB6 suppressed the expression of caspase3. The anti-inflammatory and anti-apoptotic effects of VB6 observed in LPS-treated AR42J cells are consistent with those observed in a rat model of AP. CONCLUSIONS: These results suggest that VB6 exerts anti-inflammatory and anti-apoptotic effects through inhibition of the caspase3 signaling pathway and has a protective effect against AP.

Inhibition of Pck1 in intestinal epithelial cells alleviates acute pancreatitis via modulating intestinal homeostasis.

Intestinal barrier dysfunction usually occurred in acute pancreatitis (AP) but the mechanism remains unclear. In this study, RNA sequencing of ileum in L-arginine-induced AP mice demonstrated that phosphoenolpyruvate kinase 1 (Pck1) was significantly up-regulated. Increased Pck1 expression in intestinal epithelial cells (IECs) was further validated in ileum of AP mice and duodenum of AP patients. In AP mice, level of Pck1 was positively correlated with pancreatic and ileal histopathological scores, serum amylase activity, and intestinal permeability (serum diamine oxidase (DAO), D-lactate, and endotoxin). In AP patients, level of Pck1 had a positive correlation with Ranson scores, white blood cell count and C-reactive protein. Inhibition of Pck1 by 3-Mercaptopicolinic acid hydrochloride (3-MPA) alleviated pancreatic and ileal injuries in AP mice. AP + 3-MPA mice showed improved intestinal permeability, including less epithelial apoptosis, increased tight junction proteins (TJPs) expression, decreased serum DAO, D-lactate, endotoxin, and FITC-Dextran levels, and reduced bacteria translocation. Lysozyme secreted by Paneth cells and mucin2 (MUC2) secretion in goblet cells were also partly restored in AP + 3-MPA mice. Meanwhile, inhibition of Pck1 improved intestinal immune response during AP, including elevation of M2/M1 macrophages ratio and secretory immunoglobulin A (sIgA) and reduction in neutrophils infiltration. In vitro, administration of 3-MPA dramatically ameliorated inflammation and injuries of epithelial cells in enteroids treated by LPS. In conclusion, inhibition of Pck1 in IECs might alleviate AP via modulating intestinal homeostasis.

Acute pancreatitis due to different semaglutide regimens: An updated meta-analysis.

OBJECTIVES: Some concerns persist regarding the safety of semaglutide. The objective of this updated meta-analysis is to assess the risk of acute pancreatitis with the use of semaglutide, assessing the results according to the different administration regimens. METHODS: We performed an updated meta-analysis of randomised, placebo-controlled studies of semaglutide therapy that report acute pancreatitis. This meta-analysis was performed in line with PRISMA guidelines. A global and stratified analysis according to the therapeutic scheme used was performed using the fixed-effects model. RESULTS: Twenty-one eligible trials of semaglutide, including 34,721 patients, were identified and considered eligible for the analyses. Globally, semaglutide therapy was not associated with an increased risk of acute pancreatitis (OR 0.7; 95% CI 0.5-1.2, I2 0%). When we analysed the studies according to the different schemes used, the results were similar (group with oral semaglutide: OR 0.40; 95% CI 0.10-1.60, I2 0%; group with low subcutaneous doses of semaglutide: OR 0.80; 95% CI 0.40-1.90, I2 0%; group with high subcutaneous doses of semaglutide: OR 0.70; 95% CI 0.50-1.20, I2 0%; interaction p-value=0.689). CONCLUSION: This updated meta-analysis demonstrates that the use of semaglutide is not associated with an increased risk of acute pancreatitis compared to placebo. In the stratified analysis, the results were similar with the different semaglutide regimens analysed.

Efficacy of Agmatine Treatment in Experimental Acute Pancreatitis Rat Model.

BACKGROUND/AIMS: Acute pancreatitis which is characterized by pancreatic inflammation can sometimes be difficult to treat because of limited therapeutic options. The purpose of the study was to assess the effects of agmatine in the acute pancreatitis experimental rat model. MATERIALS AND METHODS: An acute pancreatitis model was created with the administration of cerulein in 40 female Sprague-Dawley rats. Agmatine was administered as a protective agent at 5 mg/kg (low dose) and 10 mg/kg (high dose). The rats were divided into 5 groups, each with 8 rats: group 1 (acute pancreatitis); group 2 (acute pancreatitis+low-dose agmatine 5 mg/kg); group 3 (acute pancreatitis+high-dose agmatine 10 mg/kg); group 4 (placebo, acute pancreatitis+saline); and group 5 (sham and saline infusion). All rats were sacrificed 24 hours after the last injection, and the levels of superoxide dismutase, interleukin-1 beta, and tumor necrosis factor-alpha were assessed in blood samples collected via cardiac puncture. Histopathological examination was performed by a pathologist, who was blind to the groups, according to the Schoenberg's pancreatitis scoring index. RESULTS: The amylase (16.67 and 37.89 U/L), glutathione peroxidase (13.62 and 18.44 ng/mL), tumor necrosis factor-α (39.68 and 64 ng/mL), interleukin-1 (484.73 and 561.83 pg/mL), and transforming growth factor-ß (110.52 and 126.34 ng/L) levels were significantly lower and superoxide dismutase (1.29 and 0.98 ng/L) and malondialdehyde (0.99 and 0.96 nmol/mL) levels were significantly higher in group 3 compared to group 1 (P < .05). Moreover glutathione peroxidase, tumor necrosis factor-α, and transforming growth factor-ß levels were lower, and malondialdehyde levels were higher in the group 3 compared to group 2 (P < .05). Although the Schoenberg's pancreatitis scoring index was not significantly different between the high- and low-dose treatment groups, rats who received high-dose treatment had significantly lower scores compared to those with acute pancreatitis group. CONCLUSION: This is the first study that evaluated the efficacy of agmatine in an experimental model of acute pancreatitis. Agmatine, an anti-inflammatory and antioxidant agent, had a protective effect in an experimental rat model of acute pancreatitis.

Interleukin-22 Alleviates Caerulein-Induced Acute Pancreatitis by Activating AKT/mTOR Pathway.

BACKGROUND: Acute pancreatitis (AP) is one of the most common acute abdominal disorders; due to the lack of specific treatment, the treatment of acute pancreatitis, especially serious acute pancreatitis (SAP), is difficult and challenging. We will observe the changes of Interleukin -22 levels in acute pancreatitis animal models, and explore the mechanism of Interleukin -22 in acute pancreatitis. OBJECTIVE: This study aims to assess the potential protective effect of Interleukin -22 on caerulein-induced acute pancreatitis and to explore its mechanism. METHODS: Blood levels of amylase and lipase and Interleukin -22 were assessed in mice with acute pancreatitis. In animal model and cell model of caerulein-induced acute pancreatitis, the mRNA levels of P62 and Beclin-1 were determined using PCR, and the protein expression of P62, LC3-II, mTOR, AKT, p-mTOR, and p-AKT were evaluated through Western blot analysis. RESULTS: Interleukin -22 administration reduced blood amylase and lipase levels and mitigated tissue damage in acute pancreatitis mice model. Interleukin -22 inhibited the relative mRNA levels of P62 and Beclin-1, and the Interleukin -22 group showed a decreased protein expression of LC3-II and P62 and the phosphorylation of the AKT/mTOR pathway. Furthermore, we obtained similar results in the cell model of acute pancreatitis. CONCLUSION: This study suggests that Interleukin -22 administration could alleviate pancreatic damage in caerulein-induced acute pancreatitis. This effect may result from the activation of the AKT/mTOR pathway, leading to the inhibition of autophagy. Consequently, Interleukin -22 shows potential as a treatment.

Synthesis of Selenium Nanoparticles and Their Effect on Pancreatic Functions and Acute Pancreatitis in Rats.

Acute pancreatitis (AP) have been documented to have severe impact on pancreatic function. Frequent incidence of AP can result in chronic pancreatitis and thereby it can increase the probability of pancreatic cancers. This study intended to examine the effect of selenium nanoparticles (Se-NPs) synthesized from Coleus forskohlii leaf extract on pancreatic function and AP in rat. Primarily, Se-NPs was fabricated using the C. forskohlii leaf extract. The synthesized nanomaterial was characterized through UV-visible, XRD, and FTIR spectroscopies. Notably, the zeta potential of Se-NPs was found to be -32.8 mV with a polydispersity index (PDI) of 0.18. Morphological analysis on SEM unveiled the spherical shape of Se-NP with an average particle size of 12.69 nm. Strikingly, cytotoxicity analysis on pancreatic cancer and normal cells unveiled the concentration-dependent toxicity profile. However, IC 50 value is lower in normal pancreatic cell lines in comparison to pancreatic cancer cells lines. Assessment of Se-NPs on AP rats revealed the positive impact of Se-NPs. It effectively decreased the amount of lipase, amylase, IL-1ß, MDA, NO, and Bcl-2 while increased the glucose, insulin, HOMA-ß and antioxidant potential in AP rats. In addition, an evaluation of Se-NPs in the pancreatic functions revealed the non-harmful effect of Se-NPs.

Ultrasmall polyvinylpyrrolidone-modified iridium nanoparticles with antioxidant and anti-inflammatory activity for acute pancreatitis alleviation.

Acute pancreatitis (AP) is a common and serious acute inflammatory disease with high severity rate and mortality. Inflammation and oxidative stress play an extremely important role in the development of AP disease. Polyvinylpyrrolidone-modified iridium nanoparticles (IrNP-PVP) have multienzyme mimetic activity, and the aim of this article is to discuss the therapeutic alleviative effects of the ultrasmall nanozymes IrNP-PVP on AP through their antioxidant and anti-inflammatory effects. IrNP-PVP were proved to inhibit inflammation and scavenge reactive oxygen species (ROS) at the cellular level. The synthetic IrNP-PVP exhibit remarkable antioxidant and anti-inflammatory activities in the prevention and treatment of AP mice by establishing murine AP model, which can reduce the oxidative stress and inflammatory response. The results of this article indicated that the ultrasmall nanozymes IrNP-PVP effectively alleviate AP via scavenging ROS as well as suppressing inflammation both in vivo and in vitro, which might provide enormous promise for the AP management.

Encyclopaedic Review of Glipizide Pre-clinical and Clinical Status.

Glipizide is an oral glucose-lowering medication that is beneficial for the treatment of type 2 diabetes. This study compiles exhaustively all accessible information on glipizide, from preclinical to clinical studies. Glipizide may be used in concert with TRAIL to treat cancer cells; in vitro studies have shown that it suppresses angiogenesis and vasculogenesis while shielding cells from glycation-induced damage. Anticonvulsant effects and modifications in the pharmacokinetics of other medications, such as Divalproex Sodium, were seen in glipizide in vivo experiments. Propranolol amplifies glipizide's hypoglycemic effect briefly in normal animals but consistently enhances it in diabetic ones. In the treatment of cancer and neurodegenerative poly(Q) illnesses, glipizide has demonstrated to offer potential therapeutic advantages. It is ineffective in preventing DENA-induced liver cancer and may cause DNA damage over time. The way glipizide interacts with genetic variants may increase the risk of hypoglycemia. Combining Syzygium cumini and ARBE to glipizide may enhance glycemic and lipid control in type 2 diabetes. Individuals with coronary artery disease who take glipizide or glyburide have an increased risk of death. The risk of muscular responses and acute pancreatitis is minimal when glipizide and dulaglutide are combined. In conclusion, glipizide has shown promising therapeutic efficacy across a variety of disorders.

Biomimetic delivery of emodin via macrophage membrane-coated UiO-66-NH2 nanoparticles for acute pancreatitis treatment.

Acute pancreatitis (AP) is a severe inflammatory condition with a rising incidence and high mortality rates, especially in severe cases. Emodin (ED), known for its potent anti-inflammatory properties, holds promise in addressing AP. However, its clinical application is hindered by limitations such as low bioavailability and insufficient target specificity. Herein, we developed a novel drug delivery system using macrophage membrane-coated UiO-66-NH2 nanoparticles loaded with ED (MVs-UiO-ED). UiO-66-NH2 was successfully synthesized and characterized, revealing an octahedral structure with a suitable size distribution. The successful loading of ED onto UiO-66-NH2 was confirmed by ultraviolet and infrared spectroscopy. Subsequently, MVs-UiO-ED was prepared by coating macrophage membrane-derived vesicles onto UiO-ED, resulting in a biomimetic delivery system. In vitro release studies demonstrated that MVs-UiO-ED exhibited a sustained-release profile, indicating its potential for prolonged drug circulation. An AP mouse model was established to evaluate the therapeutic efficacy of MVs-UiO-ED. Compared with the model group, MVs-UiO-ED significantly reduced serum levels of α-amylase and lipase, two indicators of pancreatitis severity. Furthermore, histopathological examinations revealed that MVs-UiO-ED ameliorated pancreatic tissue damage. This study underscores the potential of MVs-UiO-ED as an effective therapeutic approach for AP.

A new onset drug induced diabetes mellitus presenting with diabetic ketoacidosis in a child undergoing treatment for B cell acute lymphoblastic leukemia. A case report and review of literature.

OBJECTIVES: Hyperglycemia is a known side effect of anticancer chemotherapeutic drugs. This entity known as drug-induced diabetes mellitus usually does not present with the development of diabetic ketoacidosis (DKA). We hereby report a case of drug induced diabetes mellitus in a child with acute leukemia presenting with DKA. CASE PRESENTATION: We report a case of a teenage boy diagnosed with B cell acute lymphoblastic leukemia and was started on induction phase chemotherapy as per the Indian Collaborative Childhood Leukemia group (ICICLe) acute lymphoblastic leukemia-14 protocol. On day 12 of the induction phase, he developed hyperglycemia and presented to us with severe diabetic ketoacidosis (DKA). Serum anti glutamic acid decarboxylase 65 antibody levels were negative with low serum C peptide levels. Initially, the possibility of drug-induced acute pancreatitis was kept which was ruled out. Keeping the possibility of drug-induced hyperglycemia, the child was started on subcutaneous regular insulin which was titrated as per sugar records. Continuation of remaining chemotherapy was done by PEGylated L-asparaginase with titration of insulin as per home-based sugar records. Insulin requirement increased from 0.3 unit/kg/day to a maximum of 1 unit/kg/day during consolidation phase 1 with PEGylated L-asparaginase suggesting drug-induced hyperglycemia but subsequently insulin requirement decreased and insulin was stopped. CONCLUSIONS: Drug induced diabetes mellitus can present as DKA during induction phase of acute lymphoblastic leukemia (ALL) chemotherapy. A high index of suspicion and close monitoring are required. The insulin requirements in these patients can be very fluctuant and may become nil during the course of treatment.

Cysteine-modified PEGylated nanoparticles for targeted delivery of methylprednisolone to pancreatitis.

The timely suppression of inflammatory mediator production and mitigation of their effects on pancreatic acinar cells are crucial for the successful management of acute pancreatitis. To achieve effective treatment, we present a novel approach utilizing cysteine modified PEG nanoparticles for both precise accumulation at the site of pancreatitis and specific targeting of acinar cells. Methylprednisolone, a nonsteroidal anti-inflammatory drug, was tailored to enhance its circulation time in the bloodstream, preferentially accumulate in the pancreas and enhance cell uptake efficiency by acinar cells through specifically targeting L-Type amino acid transporter 1. The nanosystem significantly downregulated pro-inflammatory cytokines in plasma, resulting in the effective suppression of inflammation in acinar cells within an acute pancreatitis rat model. The utilization of the dual targeted therapy strategy holds considerable potential for the clinical management of pancreatitis.

Network pharmacology and in vitro experimental verification unveil glycyrrhizin from glycyrrhiza glabra alleviates acute pancreatitis via modulation of MAPK and STAT3 signaling pathways.

Acute pancreatitis (AP) is a severe gastrointestinal inflammatory disease with increasing mortality and morbidity. Glycyrrhiza glabra, commonly known as Liquorice, is a widely used plant containing bioactive compounds like Glycyrrhizin, which possesses diverse medicinal properties such as anti-inflammatory, antioxidant, antiviral, and anticancer activities. The objective of this study is to investigate the active components, relevant targets, and underlying mechanisms of the traditional Chinese medicine Glycyrrhiza glabra in the treatment of AP. Utilizing various computational biology methods, we explored the potential targets and molecular mechanisms through Glycyrrhizin supplementation. Computational results indicated that Glycyrrhizin shows promising pharmacological potential, particularly with mitogen-activated protein kinase 3 (MAPK3) protein (degree: 70), forming stable complexes with Glycyrrhizin through ionic and hydrogen bonding interactions, with a binding free energy (ΔGbind) of -33.01 ± 0.08 kcal/mol. Through in vitro experiments, we validated that Glycyrrhizin improves primary pancreatic acinar cell injury by inhibiting the MAPK/STAT3/AKT signaling pathway. Overall, MAPK3 emerges as a reliable target for Glycyrrhizin's therapeutic effects in AP treatment. This study provides novel insights into the active components and potential targets and molecular mechanisms of natural products.

Gastrodin ameliorates acute pancreatitis by modulating macrophage inflammation cascade via inhibition the p38/NF-κB pathway.

Acute pancreatitis (AP) is a prevalent, destructive, non-infectious pancreatic inflammatory disease, which is usually accompanied with systemic manifestations and poor prognosis. Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-d-glucopyranoside) has ideal anti-inflammatory effects in various inflammatory diseases. However, its potential effects on AP had not been studied. In this study, serum biochemistry, H&E staining, immunohistochemistry, immunofluorescence, western blot, real-time quantitative PCR (RT-qPCR) were performed to investigate the effects of Gastrodin on caerulein-induced AP pancreatic acinar injury model in vivo and lipopolysaccharide (LPS) induced M1 phenotype macrophage model in vitro. Our results showed that Gastrodin treatment could significantly reduce the levels of serum amylase and serum lipase while improving pancreatic pathological morphology. Additionally, it decreased secretion of inflammatory cytokines and chemokines, and inhibited the levels of p-p38/p38, p-IκB/IκB as well as p-NF-κB p-p65/NF-κB p65. Overall our findings suggested that Gastrodin might be a promising therapeutic option for patients with AP by attenuating inflammation through inhibition of the p38/NF-κB pathway mediated macrophage cascade.

Bone Marrow Mesenchymal Stem Cells Alleviate Acute Severe Pancreatitis and Promote Lung Repair via Inhibiting NLRP3 Inflammasome in Rat.

BACKGROUND: Acute severe pancreatitis (SAP) is a severe acute abdominal disease, which can lead to pancreatic infection and necrosis as well as distant organ damage. Bone marrow mesenchymal stem cells (BMSCs) can exert anti-inflammatory effect on SAP, while NLRP3 inflammasomes play an important role in the inflammatory response. This study aimed to investigate whether BMSCs exert anti-inflammatory effect on SAP by inhibiting NLRP3 inflammasome. METHODS: The rat SAP model was established. Serum amylase, lipase and inflammatory factor levels were measured by ELISA, and the level of tissue injury was assessed by HE staining. The expression of NLRP3 inflammasome was detected by PCR, Western Blot and immunohistochemistry. ML385 was used to block Nrf2 pathway, aiming to investigate whether Nrf2 pathway was involved in the therapeutic effect of BMSCs on SAP by regulating NLRP3 inflammasome expression. RESULTS: In SAP rats, NLRP3 inflammasome was activated, which became more evident over time. After transplantation of BMSCs, the NLRP3 inflammasome expression decreased at both mRNA and protein levels, the serum levels of amylase, lipase and inflammatory factors decreased, and the pathological scores of the pancreas and lung were both improved. After blocking the Nrf2 pathway, the NLRP3 inflammasome expression increased in the injured pancreas and lung, and the inflammation deteriorated, which inhibited the therapeutic effects of BMSCs on SAP. CONCLUSION: The therapeutic effect of BMSC on SAP is at least partially ascribed to the inhibition of NLRP3 inflammasome, and Nrf2 pathway mediates the therapeutic effect of BMSC on SAP by inhibiting NLRP3 inflammasome.

Long-term outcomes and adverse effects of teduglutide in patients with short bowel syndrome: Highlighting hyperamylasemia and hyperlipasemia.

PURPOSE: Short bowel syndrome is a malabsorptive condition that occurs due to surgical removal or a congenital absence of a significant portion of the small intestine. Patients with short bowel syndrome often rely on parenteral support for extended periods or even their entire lives. Teduglutide, a glucagon-like peptide-2 analog, has shown promising results in reducing dependency on parenteral support in these patients by promoting intestinal adaptation and enhancing nutrient absorption. However, the long-term safety of teduglutide remains a concern, particularly with respect to its potential for the development of hyperamylasemia and hyperlipasemia. METHODS: This study involved patients who received teduglutide from December 2012 to December 2022 at Boston Medical Center. We evaluated outcomes and adverse events, focusing on hyperamylasemia and hyperlipasemia, through chart review. RESULTS: Thirteen eligible patients were identified who had used teduglutide. Of these, the majority (84.6%) experienced a reduction in parenteral support. A high incidence (72.7%) of nonpathological pancreatic enzyme elevation was observed in patients treated with teduglutide. These elevations were often dose dependent and were not associated with any clinical signs of acute pancreatitis or abnormal imaging findings. CONCLUSION: This study highlights the need for further investigations into the long-term safety of teduglutide and the importance of closely monitoring amylase and lipase levels in patients undergoing treatment with teduglutide.

Significant CA 19-9 elevation in IgG4-related autoimmune pancreatitis - A diagnostic dilemma.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by dense infiltration of IgG4-positive plasma cells in the affected tissue along with characteristic storiform fibrosis that can lead to the development of tumefactive lesions in any organ. CA19-9 is a marker for pancreato-biliary malignancy, however mild to moderate elevation of CA 19-9 can also be observed in IgG4-RD autoimmune pancreatitis (AIP) and sclerosing cholangitis (IgG4-SC). Therefore, it becomes difficult to differentiate between these entities. We describe the case of a 65-year-old male with history of IgG4-RD, presenting with jaundice and abdominal pain. He was found to have a pancreatic mass with significantly elevated IgG4 162 (2-96 mg/dL and CA19-9 levels 2830 (0-35 U/ml). Patient underwent ERCP and biopsy, which ruled out pancreatic cancer and cholangiocarcinoma. He was diagnosed with IgG4-RD autoimmune pancreatitis (AIP) and sclerosing cholangitis. Treatment with steroids and rituximab resulted in significant improvement in the bilirubin and a dramatic decrease in CA19-9 levels.

Real-World Patient Experience With Pancreatic Enzyme Replacement Therapy in the Treatment of Exocrine Pancreatic Insufficiency.

OBJECTIVES: This study aimed to provide patients insights on the management of exocrine pancreatic insufficiency (EPI) with pancreatic enzyme replacement therapy (PERT). MATERIALS AND METHODS: A survey of 75 members of Inspire's Pancreatitis or Pancreatic Cancer Support communities was conducted. Eligibility included having EPI secondary to chronic pancreatitis, pancreatic cancer, pancreatic surgery, or acute pancreatitis, and current/past PERT experience. RESULTS: Patients were 73% female, 57% aged 50 to 69 years, and 85% White, with PERT prescribed by a gastroenterologist/pancreatologist for 64%. Only approximately half of respondents agreed that their healthcare provider provided detailed information about EPI (54%) or how PERT works to treat EPI (56%). Most respondents (83%) reported searching for information about EPI, 56% were taking PERT solely before or after eating, 36% reported taking suboptimal PERT doses, and 39% reported no follow-up. In addition, 24% decreased their PERT dosage without consulting their physician, and 21% reported purposely skipping PERT. CONCLUSIONS: This study reveals potential barriers to effective treatment of EPI with PERT, including lack of patient education, mainly how and when to take PERT, gaps in appropriate dosing, and lack of patient follow-up. Continued focus on patient and provider education is essential to address these gaps and optimize the treatment of EPI.

KAN0438757, a novel PFKFB3 inhibitor, prevent the progression of severe acute pancreatitis via the Nrf2/HO-1 pathway in infiltrated macrophage.

Acute pancreatitis (AP) is a non-infectious pancreatic enzyme-induced disorder, a life-threatening inflammatory condition that can cause multi-organ dysfunction, characterized by high morbidity and mortality. Several therapies have been employed to target this disorder; however, few happen to be effectively employable even in the early phase. PFKFB3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) is a critical regulator of glycolysis and is upregulated under inflammatory, mitogenic, and hypoxia conditions. Essential information on the targeting of the inflammatory pathway will present the termination of the disorder and recovery. Herein we investigated the protective function of KAN0438757, a potent inhibitor of PFKFB3, and its mechanism of impeding AP induced in mice. KAN0438757 was confirmed to activate the Nrf2/HO-1 inflammatory signaling pathways in response to caerulein induced acute pancreatitis (CAE-AP) and fatty acid ethyl ester induced severe acute pancreatitis (FAEE-SAP). Additionally, KAN0438757 alleviated the inflammatory process in infiltrated macrophage via the Nrf2/HO-1 inflammatory signaling pathway and demonstrated a significant effect on the growth of mice with induced AP. And more importantly, KAN0438757 displayed negligible toxicity in vivo. Taken together our data suggest KAN0438757 directly suppresses the inflammatory role of PFKFB3 and induces a protective role via the Nrf2/HO-1 pathway, which could prove as an excellent therapeutic platform for SAP amelioration.

Tectoridin alleviates caerulein-induced severe acute pancreatitis by targeting ERK2 to promote macrophage M2 polarization.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas with a high mortality rate. Macrophages play a crucial role in the pathogenesis of pancreatitis. Tectoridin (Tec) is a highly active isoflavone with anti-inflammatory pharmacological activity. However, the role of Tec in the SAP process is not known. The purpose of this study was to investigate the therapeutic effect and potential mechanism of Tec on SAP. To establish SAP mice by intraperitoneal injection of caerulein and Lipopolysaccharide (LPS), the role of Tec in the course of SAP was investigated based on histopathology, biochemical indicators of amylase and lipase and inflammatory factors. The relationship between Tec and macrophage polarization was verified by immunofluorescence, real-time quantitative PCR and Western blot analysis. We then further predicted the possible targets and signal pathways of action of Tec by network pharmacology and molecular docking, and validated them by in vivo and in vitro. In this study, we demonstrated that Tec significantly reduced pancreatic injury in SAP mice, and decreased serum levels of amylase and lipase. The immunofluorescence and Western blot analysis showed that Tec promoted macrophage M2 polarization. Network pharmacology and molecular docking predicted that Tec may target ERK2 for the treatment of SAP, and in vivo and in vitro experiments proved that Tec inhibited the ERK MAPK signal pathway. In summary, Tec can target ERK2, promote macrophage M2 polarization and attenuate pancreatic injury, Tec may be a potential drug for the treatment of SAP.

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis.

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.