Involvement of heparanase in the pathogenesis of acute pancreatitis: Implication of novel therapeutic approaches.

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.

Chaiqin chengqi decoction treatment mitigates hypertriglyceridemia-associated acute pancreatitis by modulating liver-mediated glycerophospholipid metabolism.

BACKGROUND: The incidence of hypertriglyceridemia-associated acute pancreatitis (HTG-AP) is increasing globally and more so in China. The characteristics of liver-mediated metabolites and related key enzymes are rarely reported in HTG-AP. Chaiqin chengqi decoction (CQCQD) has been shown to protect against AP including HTG-AP in both patients and rodent models, but the underlying mechanisms in HTG-AP remain unexplored. PURPOSE: To assess the characteristics of liver-mediated metabolism and the therapeutic mechanisms of CQCQD in HTG-AP. METHODS: Male human apolipoprotein C3 transgenic (hApoC3-Tg; leading to HTG) mice or wild-type littermates received 7 intraperitoneal injections of cerulein (100 µg/kg) to establish HTG-AP and CER-AP, respectively. In HTG-AP, some mice received CQCQD (5.5 g/kg) gavage at 1, 5 or 9 h after disease induction. AP severity and related liver injury were determined by serological and histological parameters; and underlying mechanisms were identified by lipidomics and molecular biology. Molecular docking was used to identify key interactions between CQCQD compounds and metabolic enzymes, and subsequently validated in vitro in hepatocytes. RESULTS: HTG-AP was associated with increased disease severity indices including augmented liver injury compared to CER-AP. CQCQD treatment reduced severity and liver injury of HTG-AP. Glycerophospholipid (GPL) metabolism was the most disturbed pathway in HTG-AP in comparison to HTG alone. In HTG-AP, the mRNA level of GPL enzymes involved in phosphocholine (PC) and phosphatidylethanolamine (PE) synthesis (Pcyt1a, Pcyt2, Pemt, and Lpcat) were markedly upregulated in the liver. Of the GPL metabolites, lysophosphatidylethanolamine LPE(16:0) in serum of HTG-AP was significantly elevated and positively correlated with the pancreas histopathology score (r = 0.65). In vitro, supernatant from Pcyt2-overexpressing hepatocytes co-incubated with LPE(16:0) or phospholipase A2 (a PC- and PE-hydrolyzing enzyme) alone induced pancreatic acinar cell death. CQCQD treatment downregulated PCYT1a and PCYT2 enzyme levels in the liver. Hesperidin and narirutin were identified top two CQCQD compounds with highest affinity docking to PCYT1a and PCYT2. Both hesperidin and narirutin reduced the level of some GPL metabolites in hepatocytes. CONCLUSION: Liver-mediated GPL metabolism is excessively activated in HTG-AP with serum LPE(16:0) level correlating with disease severity. CQCQD reduces HTG-AP severity partially via modulating key enzymes in GPL metabolism pathway.

Clinical efficacy of ilaprazole combined with somatostatin on severe acute pancreatitis and the effects on oxidative stress and inflammatory response.

This study investigates the clinical efficacy of ilaprazole combined with somatostatin on severe acute pancreatitis (SAP) and the effects on oxidative stress and inflammatory response. Seventy SAP patients were randomized to the control and observation groups, which received the somatostatin treatment and ilaprazole combined with somatostatin treatment for seven days, respectively. Results found that, the time of abdominal pain relief, time of serum amylase recovery, time of urinary amylase recovery and time of defecation recovery in the observation group were shorter than those in the control group (P<0.05). After the treatment, comparing to the control group, in the observation group the heart rate decreased (P<0.05), the mean arterial pressure and the central venous pressure increased (P<0.05), the serum levels of super oxide dismutase and glutathione peroxidase increased (P<0.05) and the serum levels of malondialdehyde, tumor necrosis factor α, interleukin-6, C-reactive protein decreased (P<0.05). In treatment of SAP, ilaprazole combined with somatostatin can enhance the curative efficacy and decrease the oxidative stress and the inflammatory response in patients. In addition, it cannot increase the adverse reactions, with good safety.

The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice.

In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.

DGA ameliorates severe acute pancreatitis through modulating macrophage pyroptosis.

Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14ß-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1ß. DGA significantly reduced the protein expression of IL-1ß and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP.

Effectiveness and safety of low molecular weight heparin in the management of acute pancreatitis: a systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that low-molecular-weight heparin (LMWH) may play a role in mitigating the severity of acute pancreatitis (AP). This systematic review and meta-analysis aims to synthesise existing evidence on the effectiveness and safety of LMWH in the treatment of moderately-severe and severe AP. METHODS: This systematic review and meta-analysis was conducted in accordance with the 2020 update of the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The systematic search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, Scopus, and EMBASE, covering studies published up to February 2024. Randomised controlled trials (RCTs) and observational studies (n-RCTs) that reported the differences in the outcomes of AP for patients receiving LMWH in addition to the standard treatment (Intervention), compared to patients managed by standard treatment without LMWH (Control) were eligible. A random-effects model was used to calculate the pooled relative risk (RR) and mean differences (MD) with the corresponding 95% CI. RESULTS: Thirteen studies were included in the meta-analysis, all published between 2004 and 2022. Eight studies were RCTs, and five were n-RCTs. Data from 13,709 patients (6.971 Interventions and 6.738 Controls) were analysed. The comparison of Intervention and Control groups showed the superiority of LMWH to standard treatments in terms of overall mortality (RR = 0.44, 95% CI = 0.31; 0.64, P < 0.0001, I2 = 51%), acute necrotic collections (RR = 0.24, 95% CI = 0.09; 0.62, P = 0.003, I2 = 0%), and organ failure (RR = 0.67, 95% CI = 0.48; 0.93, P = 0.02, I2 = 78%). The Intervention group showed superior outcomes compared with the Control group for gastrointestinal bleeding (RR = 0.64, 95% CI = 0.44; 0.94, P = 0.02, I2 = 0%), length of hospital stay (MD= - 6.08, 95% CI = - 10.08; - 2.07, P = 0.003, I2 = 98%), need for operative interventions (RR = 0.50, 95% CI = 0.29; 0.87, P = 0.01, I2 = 61%), and vascular thrombosis (RR = 0.43, 95% CI = 0.31; 0.61, P < 0.00001, I2 = 0%). CONCLUSIONS: Moderate to high-quality evidence suggests that early intervention with LMWH could improve the prognosis of non-mild AP in terms of mortality, organ failure, and decreased incidence of vascular thrombosis. In light of our findings, integrating LMWH into the treatment regimen for moderate-severe to severe AP is advocated.

Network pharmacological mechanism analysis and evidence-based medical validation of Dahuang Mudan Decoction in the treatment of acute pancreatitis.

BACKGROUND: Dahuang Mudan Decoction is commonly used in China for the treatment of acute pancreatitis. Nevertheless, the therapeutic efficacy of the drug remains a subject of debate, and its active ingredients and potential therapeutic targets remain to be determined. The present study used a network pharmacological approach to investigate the active ingredients and possible targets of the drug, and illustrated the clinical effectiveness of Dahuang Mudan Decoction in the treatment of acute pancreatitis by meta-analysis. METHODS: The present study investigated the active ingredients of the constituent herbs of Dahuang Mudan Decoction using the TCMID database. In order to further identify molecular targets, Swiss Target Prediction, OMIM and Genecards databases was be used. The present study used metascape database for gene ontology function enrichment analysis and Kyoto Genome Encyclopedia pathway enrichment analysis. A gene interaction network diagram was established for predicting the main targets and mechanism of action to Dahuang Mudan Decoction for acute pancreatitis. To further illustrate the validity of the gene targets and the clinical efficacy of the drug, 13 relevant studies were included for meta-analysis and analyzed using the Cochrane Collaboration's Review Manager 5.4 software. RESULT: After a thorough screening process, the present study identified three main components of Dahuang Mudan Decoction: kaempferol, quercetin and eupatin. These three major components have the potential to target 5 important proteins: AKT1, TNF-a, IL-6, TP53, HIF1A. In addition, pathway analyses by the Kyoto Genome Encyclopedia showed that Dahuang Mudan Decoction is active through the Pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, etc signaling pathway to act on acute pancreatitis. The results of meta-analysis showed that compared with the control group, the experimental group had superior performance in terms of overall treatment efficacy, reduction of hospital stays and inflammatory factor levels after treatment. CONCLUSION: In summary, network pharmacological studies have shown that Dahuang Mudan Decoction affects acute pancreatitis through different components, targets, and mechanisms. In addition, the meta-analysis study strongly supported the effectiveness of Dahuang Mudan Decoction in the treatment of acute pancreatitis.

Bufalin alleviates inflammatory response and oxidative stress in experimental severe acute pancreatitis through activating Keap1-Nrf2/HO-1 and inhibiting NF-κB pathways.

Severe acute pancreatitis (SAP) is a prevalent acute inflammatory disease that is clinically manifested by systemic inflammation dysregulation, resulting in a significantly elevated mortality rate. Bufalin has been verified to have potent pharmacological properties, including analgesic, anti-tumor and anti-inflammatory effects. However, it remains unclear whether bufalin inhibits SAP. Thus, we aim to explore the impact of bufalin in SAP rats and to evaluate the potential mechanisms of action. In addition to analyzing serum biochemistry and pancreatic tissue pathology, we elucidated its mechanisms of action through enzyme-linked immunosorbent assay (ELISA), immunohistochemical analysis, Western blot, and quantitative real-time PCR. The results demonstrated that bufalin dose-dependently reversed the elevation of serum Amylase (Amy) and Lipase (LPS) levels in SAP rats, alleviating pancreatic tissue pathological damage. Bufalin exhibited potent antioxidant effects by reducing malondialdehyde (MDA) levels, decreasing Superoxide dismutase (SOD) and glutathione(GSH) consumption, inhibiting the interaction of Keap1-Nrf2, and increasing HO-1 expression. Furthermore, bufalin inhibited TNF-α, IL-6, IL-1ß, p-NF-κB-p65, p-IκBα, and NF-κB-p65 expression, while enhancing IκBα expression, ultimately confirming its anti-inflammatory effects on SAP. In summary, our findings suggest that bufalin exerts anti-inflammatory and antioxidant actions in NaT-SAP rats by inhibiting NF-κB and activating the Keap1-Nrf2/HO-1 pathway. This study represents the inaugural application of bufalin in NaT-induced SAP rats, indicating its potential as an effective therapeutic agent for SAP patients.

Olezarsen, a liver-directed APOC3 ASO therapy for hypertriglyceridemia.

INTRODUCTION: Apolipoprotein (apo)C-III, a key regulator of plasma triglyceride (TG) levels, is a prime candidate for the treatment of hypertriglyceridemia (HTG), prevention of acute pancreatitis, and reduction of future atherosclerotic cardiovascular disease (ASCVD) events. AREAS COVERED: We discuss the role of apoC-III as a therapeutic target for HTG, describe the pharmacodynamics, pharmacokinetics, and metabolism of olezarsen, as well as report on the findings of recent clinical trials with this liver-directed APOC3 antisense oligonucleotide (ASO). EXPERT OPINION: Olezarsen, a GalNac-conjugated ASO targeting apoC-III, can reduce TG levels by ~ 50% in patients with extreme HTG due to familial chylomicronemia syndrome, as well as in patients with moderate HTG. Attention is now focused on whether olezarsen reduces ASCVD risk in patients with moderate and severe HTG. While olezarsen does cause elevations in liver enzymes, these changes are not clinically meaningful, and are not associated with thrombocytopenia, an issue with its predecessor, volanesorsen. The need for 4-weekly administration puts olezarsen at a disadvantage to competing injectables. Results from the CORE, CORE2, and ESSENCE phase III clinical trials in patients with severe HTG, expected in the second half of 2025, will help determine the requirement for a larger cardiovascular outcomes trial.

Natural Compounds for the Treatment of Acute Pancreatitis: Novel Anti-Inflammatory Therapies.

Acute pancreatitis remains a serious public health problem, and the burden of acute pancreatitis is increasing. With significant morbidity and serious complications, appropriate and effective therapies are critical. Great progress has been made in understanding the pathophysiology of acute pancreatitis over the past two decades. However, specific drugs targeting key molecules and pathways involved in acute pancreatitis still require further study. Natural compounds extracted from plants have a variety of biological activities and can inhibit inflammation and oxidative stress in acute pancreatitis by blocking several signaling pathways, such as the nuclear factor kappa-B and mitogen-activated protein kinase pathways. In this article, we review the therapeutic effects of various types of phytochemicals on acute pancreatitis and discuss the mechanism of action of these natural compounds in acute pancreatitis, aiming to provide clearer insights into the treatment of acute pancreatitis.

Emodin alleviates lung injury via the miR-217-5p/Sirt1 axis in rats with severe acute pancreatitis.

Acute lung injury (ALI) is closely related to high mortality in severe acute pancreatitis (SAP). This study unveils the therapeutic effect and mechanism of miR-217-5p on SAP-associated ALI. The miR-217-5p RNA expression was significantly up-regulated in lipopolysaccharide (LPS)-stimulated primary rat alveolar epithelial type II cells (AEC II) and sodium taurocholate-treated pancreas and lung in SAP rats. miR-217 inhibition protected AEC II from LPS-induced damage by inhibiting apoptosis and reducing the TNF-α, IL-6, and ROS levels. miR-217 inhibition suppressed apoptosis and alleviated mitochondrial damage through mitochondria-mediated apoptotic pathway in vitro. Sirt1 is a direct target of miR-217-5p. Dual-luciferase reporter assay confirmed the binding of miR-217-5p to Sirt1 mRNA 3'-UTR. The rescue experiment identified that the anti-apoptotic, anti-inflammatory, and anti-oxidative effects of miR-217 inhibition were mediated by Sirt1 in vitro. Emodin (EMO) protected AEC II from LPS-induced damage and alleviated pancreatic and lung tissue injuries. EMO exerted similar effects as miR-217 inhibition in vitro and in vivo. The effects of EMO were abolished by miR-217 overexpression. In conclusion, miR-217-5p inhibition exerts protective effects on SAP-ALI in vitro and in vivo by repressing apoptosis, inflammation, and oxidative stress through Sirt1 activation. EMO protects against lung injuries in SAP-associated ALI rats through miR-217-5p/Sirt1 axis.

Pancreas and pancreatitis: Exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI) is highly prevalent among individuals with cystic fibrosis (CF). Individuals diagnosed with EPI are often labeled as having "pancreas insufficient cystic fibrosis (PI-CF)" while those with normal exocrine function are labeled as "pancreas sufficient CF (PS-CF)." This diagnosis of EPI relies on clinical and laboratory features and management involves consumption of pancreas enzyme replacement therapy. In this review, we discuss the nuances of diagnosis and management of EPI in CF. We also present emerging evidence on the effects of CFTR modulating agents on the management of EPI, and speculate that these medications may lead to greater heterogeneity in management of EPI in CF moving forward.

Protective effects of forsythoside A against severe acute pancreatitis- induced brain injury in mice.

OBJECTIVES: This study aimed to evaluate the therapeutic effects of forsythoside A (FA) on brain injury induced by severe acute pancreatitis (SAP) using a murine model. METHODS: Mice were induced with 3.5 % sodium taurocholate to model SAP-induced brain injury (SAP-IBI) and were randomly assigned to four distinct treatment regimens: the SAP-IBI model group (SAP-IBI), low-dose FA treatment group (FA L+SI), middle-dose FA treatment group (FA M+SI), and high-dose FA treatment group (FA H+SI). A sham-operation group (SO) served as a negative control. Serum levels of interleukin-1ß (IL-1ß) and IL-18 were quantified via ELISA, and serum amylase levels were assessed using optical turbidimetry. mRNA expression levels of AIM2, ASC, Caspase-1, and GAPDH in hippocampal brain tissue were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Protein levels of NLRP3, GSDMD, IL-1ß, and IL-18 in hippocampal brain tissue were evaluated using Western blotting. Neurological function in surviving mice was assessed through modified neurological severity scores (mNSS). Transmission electron microscopy (TEM) provided ultrastructural analysis of the hippocampus. Additionally, water content and pathological changes in hippocampal brain tissue were examined 24 hours post-operation, along with other relevant indicators. RESULTS: At 24 hours post-operation, the FA H+SI group exhibited significantly reduced levels of serum amylase, IL-1ß, and IL-18, along with decreased expression of AIM2, ASC, and Caspase-1 mRNA. Furthermore, NLRP3 protein levels, water content, pancreas and hippocampal brain pathological scores, and mNSS were significantly lower compared to the SAP-IBI group (P<0.01). CONCLUSIONS: FA demonstrates protective effects against SAP-IBI in mice, suggesting potential therapeutic benefits.

Global trends in opioid use for pain management in acute pancreatitis: A multicentre prospective observational study.

BACKGROUND: Since there is no current international consensus on the optimal approach for pain management in acute pancreatitis (AP), analgesic practices may vary across different healthcare settings. OBJECTIVE: This study explored global disparities in analgesic use, in particular opioids, during admission and at discharge in hospitalised AP patients. METHODS: This was a post hoc analysis of the prospective PAINAP database, which included all admissions for AP between April and June 2022 with a 1-month follow-up. Demographic details, analgesic use, and clinical outcomes were recorded during admission and at discharge. Odds ratios (ORs) for opioid use during admission and at discharge were identified using multivariable regression analyses. RESULTS: Amongst the 1864 patients (52% males, median age 56 (interquartile range, 41-71)) across three different continents, simple analgesics were predominantly used as the primary analgesic (70%). Opioid use during admission was lowest in European centres (67%). Admission in Asian (OR, 2.53 (95% confidence interval (CI), 1.59-4.04), p < 0.001), and Australian (OR, 5.81 (95% CI, 3.19-10.56), p < 0.001) centres was associated with opioid administration during admission compared with European centres. Increased pain severity, longer pre-admission pain duration, organ failure, and longer length of admission increased opioid use during admission. At discharge, Asian (OR, 2.01 (95% CI, 1.40-2.88), p < 0.001) and Australian (OR, 1.91 (95% CI, 1.28-2.85), p = 0.002) centres were associated with opioid prescription compared with European centres. Increased pain severity, longer pre-admission pain duration, acute necrotic collections, and walled-off necrosis also increased the likelihood of opioid prescription at discharge. CONCLUSION: There are substantial intercontinental differences in opioid use for AP pain. Accordingly, there is a need for international guidelines on pain management in AP.

Biomimetic Trypsin-Responsive Structure-Bridged Mesoporous Organosilica Nanomedicine for Precise Treatment of Acute Pancreatitis.

Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin's ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca2+ chelator BAPTA-AM with a high loading content (∼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs' skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.

Certolizumab Has Favorable Efficacy on Preventing Pancreas and Target Organs Damage in Acute Pancreatitis.

OBJECTIVE: It was targeted to assess the efficacy of certolizumab on pancreas and target organs via biochemical parameters and histopathologic scores in experimental acute pancreatitis (AP). MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into the following 5 equal groups: group 1 (sham group), group 2 (AP group), group 3 (AP + low-dose certolizumab group), group 4 (AP + high-dose certolizumab group), and group 5 (placebo group). Rats in all groups were sacrificed 24 hours after the last injection and amylase, tumor necrosis factor α, transforming growth factor ß, interleukin 1ß, malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were studied in blood samples. Histopathological investigation of both the pancreas and target organs (lungs, liver, heart, kidneys) was performed by a pathologist blind to the groups. In silico analysis were also accomplished. RESULTS: The biochemical results in the certolizumab treatment groups were identified to be significantly favorable compared to the AP group (P < 0.001). The difference between the high-dose group (group 4) and low-dose treatment group (group 3) was found to be significant in terms of biochemical parameters and histopathological scores (P < 0.001). In terms of the effect of certolizumab treatment on the target organs (especially on lung tissue), the differences between the low-dose treatment group (group 3) and high-dose treatment group (group 4) with the AP group (group 2) were significant. CONCLUSIONS: Certolizumab has favorable protective effects on pancreas and target organs in AP. It may be a beneficial agent for AP treatment and may prevent target organ damage.

Combination of the CRAC Channel Inhibitor CM4620 and Galactose as a Potential Therapy for Acute Pancreatitis.

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of Ca2+ release-activated Ca2+ (CRAC) channels has been proposed as a potential treatment, and currently, a novel selective CRAC channel inhibitor CM4620 (Auxora, CalciMedica) is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here, we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 n m, have been studied against necrosis induced by bile acids, palmitoleic acid, or l-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 n m and palmitoleic acid starting from 1 n m. Combining CM4620 and galactose (1 m m) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acid-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced edema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 m m) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.

Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production.

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/ß-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.

Mechanism Investigation and Clinical Retrospective Evaluation of Qingyi Granules: Pancreas Cleaner About Ameliorating Severe Acute Pancreatitis with Acute Respiratory Distress Syndrome.

Background: Despite its extensive utilization in Chinese hospitals for treating acute pancreatitis (AP) and related acute respiratory distress syndrome (ARDS), the active components and mechanisms underlying the action of Qingyi Granule (QYKL) remain elusive. Methods: This study consists of four parts. First, we used Mendelian randomization (MR) to investigate the causal relationship between AP, cytokine, and ARDS. Next, 321 patients were collected to evaluate the efficacy of QYKL combined with dexamethasone (DEX) in treating AP. In addition, we used UHPLC-QE-MS to determine the chemical constituents of QYKL extract and rat serum after the oral administration of QYKL. The weighted gene coexpression network analysis (WGCNA) method was used to find the main targets of AP-related ARDS using the GSE151572 dataset. At last, a AP model was established by retrograde injection of 5% sodium taurocholate. Results: MR showed that AP may have a causal relationship with ARDS by mediating cytokine storms. Retrospective study results showed early administration of QYKL was associated with a lower incidence of ARDS, mortality, admissions to the intensive care unit, and length of stay in AP patients compared to the Control group. Furthermore, we identified 23 QYKL prototype components absorbed into rat serum. WGCNA and differential expression analysis identified 1558 APALI-related genes. The prototype components exhibited strong binding activity with critical targets. QYKL has a significant protective effect on pancreatic and lung injury in AP rats, and the effect is more effective after combined treatment with DEX, which may be related to the regulation of the IL-6/STAT3 signaling pathway. Conclusion: By integrating MR, retrospective analysis, and systematic pharmacological methodologies, this study systematically elucidated the therapeutic efficacy of QYKL in treating AP-related ARDS, establishing a solid foundation for its medicinal use.

Irisin Ameliorate Acute Pancreatitis and Acinar Cell Viability through Modulation of the Unfolded Protein Response (UPR) and PPARγ-PGC1α-FNDC5 Pathways.

Acute pancreatitis (AP) entails pancreatic inflammation, tissue damage and dysregulated enzyme secretion, including pancreatic lipase (PL). The role of irisin, an anti-inflammatory and anti-apoptotic cytokine, in AP and exocrine pancreatic stress is unclear. We have previously shown that irisin regulates PL through the PPARγ-PGC1α-FNDC5 pathway. In this study, we investigated irisin and irisin's pathway on AP in in vitro (AR42J-B13) and ex vivo (rat primary acinar) models using molecular, biochemical and immunohistochemistry methodology. Pancreatitis induction (cerulein (cer)) resulted in a significant up-regulation of the PPARγ-PGC1α-FNDC5 axis, PL expression and secretion and endoplasmic reticulum (ER) stress unfolded protein response (UPR) signal-transduction markers (CHOP, XBP-1 and ATF6). Irisin addition in the cer-pancreatitis state resulted in a significant down-regulation of the PPARγ-PGC1α-FNDC5 axis, PPARγ nucleus-translocation and inflammatory state (TNFα and IL-6) in parallel to diminished PL expression and secretion (in vitro and ex vivo models). Irisin addition up-regulated the expression of pro-survival UPR markers (ATF6 and XBP-1) and reduced UPR pro-apoptotic markers (CHOP) under cer-pancreatitis and induced ER stress (tunicamycin), consequently increasing cells viability. Irisin's pro-survival effect under cer-pancreatitis state was abolished under PPARγ inhibition. Our findings suggest irisin as a potential therapeutic option for AP via its ability to up-regulate pro-survival UPR signals and activate the PPARγ-PGC1α-FNDC5 pathway.