Isorhamnetin Alleviates Mitochondrial Injury in Severe Acute Pancreatitis via Modulation of KDM5B/HtrA2 Signaling Pathway.

Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis and the absence of effective treatment options. Isorhamnetin (ISO), a naturally occurring flavonoid, demonstrates robust antioxidant and anti-inflammatory properties intricately linked to the modulation of mitochondrial function. However, the specific protective impact of ISO on SAP remains to be fully elucidated. In this study, we demonstrated that ISO treatment significantly alleviated pancreatic damage and reduced serum lipase and amylase levels in the mouse model of SAP induced by sodium taurocholate (STC) or L-arginine. Utilizing an in vitro SAP cell model, we found that ISO co-administration markedly prevented STC-induced pancreatic acinar cell necrosis, primarily by inhibiting mitochondrial ROS generation, preserving ATP production, maintaining mitochondrial membrane potential, and preventing the oxidative damage and release of mitochondrial DNA. Mechanistically, our investigation identified that high-temperature requirement A2 (HtrA2) may play a central regulatory role in mediating the protective effect of ISO on mitochondrial dysfunction in STC-injured acinar cells. Furthermore, through an integrated approach involving bioinformatics analysis, molecular docking analysis, and experimental validation, we uncovered that ISO may directly impede the histone demethylation activity of KDM5B, leading to the restoration of pancreatic HtrA2 expression and thereby preserving mitochondrial function in pancreatic acinar cells following STC treatment. In conclusion, this study not only sheds new light on the intricate molecular complexities associated with mitochondrial dysfunction during the progression of SAP but also underscores the promising value of ISO as a natural therapeutic option for SAP.

The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis.

Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.

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.

Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) protocol and statistical analysis plan: a prospective, multicentre, double-blind, randomized, placebo controlled clinical trial.

INTRODUCTION: Acute pancreatitis is a common disease which, in its severe form, is associated with significant morbidity and mortality. Currently, there is no specific therapy known to attenuate organ failure in severe pancreatitis and treatment consists primarily of supportive care. Corticosteroids have been shown to be beneficial in disease processes associated with systemic inflammation and could potentially improve outcomes in severe acute pancreatitis. METHODS: The Corticosteroids to Reduce Inflammation in Severe Pancreatitis (CRISP) trial is a multi-centre, double-blind, randomized, placebo-controlled clinical trial that aims to determine the impact of corticosteroids versus placebo on organ injury in patients with severe acute pancreatitis. Patients are randomized to receive 100 mg of hydrocortisone parenterally versus matching placebo every 8 h for 3 days. Clinical and laboratory data are collected at the time of study enrollment, at 24, 48 and 72 h. The primary end-point for the trial is the difference in 72-h change in the Sequential Organ Failure Assessment (SOFA) score between hydrocortisone and placebo groups. Additional key secondary outcomes include ventilator free days and 28-day mortality. DISCUSSION: This study will add to the evidence base in the treatment of severe acute pancreatitis. The results will inform clinical practice and future studies in the field. Trial registration number The trial is registered on clinicaltrials.gov (NCT05160506). It was posted on December 16th, 2021. The study protocol was approved by the Beth Israel Deaconess Medical Center Committee on Clinical Investigation (CCI) (protocol 2021 P-000803).

Manejo de la analgesia en la pancreatitis aguda. Resultados de una encuesta nacional / Management of analgesia in acute pancreatitis: Results of a national survey

Introducción La pancreatitis aguda constituye uno de los principales motivos de ingreso por causa digestiva. En su manejo resulta crucial un adecuado tratamiento del dolor. Pero apenas existen descripciones sobre las pautas analgésicas empleadas en nuestro medio. Métodos Encuesta on-line sobre el manejo de analgésicos en la pancreatitis aguda, dirigida a médicos adjuntos y residentes con ejercicio en España. Resultados Un total de 209 facultativos de 88 centros respondieron la encuesta. El 90% eran especialistas en Aparato Digestivo y el 69% trabajaba en un centro terciario. La mayoría (64,4%) no utilizan habitualmente escalas para medir el dolor. Al elegir un fármaco se valora sobre todo la experiencia en su uso. Los tratamientos más prescritos inicialmente son: combinación de paracetamol y metamizol (53,5%), paracetamol solo (19,1%) y metamizol solo (17,4%). Como rescate: meperidina (54,8%), tramadol (17,8%), cloruro mórfico (17,8%) y metamizol (11,5%). Se utiliza perfusión continua en el 8,2% de los tratamientos iniciales. Los médicos con >10años de servicio utilizan más metamizol en monoterapia (50%), mientras que médicos residentes y adjuntos con <10años de servicio lo prescriben asociado a paracetamol (85%). Si se necesita progresar, se usan fundamentalmente cloruro mórfico y meperidina. La especialidad del encuestado, el tamaño del centro de trabajo y la unidad/servicio donde ingresaban los pacientes no influyeron sobre la analgesia pautada. El grado de satisfacción con el tratamiento del dolor alcanzó el 7,8/10 (DE 0,98). Conclusión En nuestro medio, el metamizol y el paracetamol son los analgésicos más empleados como tratamiento inicial del dolor en la pancreatitis aguda, y la meperidina, el analgésico de rescate más utilizado (AU)

Introduction Acute pancreatitis is one of the main reasons for digestive admissions. Adequate pain treatment is crucial in its management. However, there are hardly any descriptions of the analgesic guidelines used in our setting. Methods On-line survey on analgesic management in acute pancreatitis, aimed at attending physicians and residents practising in Spain. Results Two hundred and nine physicians from 88 centres responded to the survey. Ninety percent were specialists in gastrointestinal medicine and 69% worked in a tertiary centre. The majority (64.4%) do not routinely use scales to measure pain. When choosing a drug, experience in its use was the most important factor. The most commonly prescribed initial treatments are: combination of paracetamol and metamizole (53.5%), paracetamol alone (19.1%) and metamizole alone (17.4%). As rescue: meperidine (54.8%), tramadol (17.8%), morphine chloride (17.8%) and metamizole (11.5%). Continuous perfusion is used in 8.2% of initial treatments. Physicians with >10 years of service use more metamizole as monotherapy (50%), while residents and attending physicians with <10 years of service prescribe it in combination with paracetamol (85%). If progression is needed, morphine chloride and meperidine are mainly used. The speciality of the respondent, the size of the work centre and the unit/service where the patients were admitted did not influence the analgesia prescribed. Satisfaction with pain management reached 7.8/10 (SD 0.98). Conclusion In our setting, metamizole and paracetamol are the most commonly used analgesics as initial pain treatment in acute pancreatitis, and meperidine is the most commonly used rescue analgesic. (AU)

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.

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.

A Good Prognosis of Patients with Acute Pancreatitis Combined with Pulmonary Embolism: Early Identification and Intervention.

BACKGROUND: Pulmonary embolism (PE) is a relatively rare vascular complication of acute pancreatitis (AP), and its mortality rate is high. To our knowledge, relevant literature reports still need to be summarized. In this study, we analyzed the clinical characteristics, treatment, and prognosis of five patients with AP complicated by PE and summarized and reviewed the relevant literature. METHODS: Clinical data of patients with AP complicated by PE treated in Taizhou Hospital of Zhejiang Province between January 2017 and September 2022 were retrospectively collected. Combined with the relevant literature, the clinical characteristics, treatment, and prognoses of patients with AP combined with PE were analyzed and summarized. RESULTS: Five patients were eventually enrolled in this study. Among the five patients with AP complicated by PE, all (100%) had symptoms of malaise, primarily chest tightness, shortness of breath, and dyspnea. All patients (100%) had varied degrees of elevated D-dimer levels and a significant decrease in the pressure of partial oxygen (PO2) and pressure of arterial oxygen to fractional inspired oxygen concentration ratio (PaO2/FiO2). Computed tomographic angiography (CTA) or pulmonary ventilation/perfusion imaging revealed a pulmonary artery filling defect in these patients. One patient (20%) had left calf muscular venous thrombosis before the occurrence of PE. Four patients (80%) were treated with lowmolecular- weight heparin (LMWH), and one patient (20%) was treated with rivaroxaban during hospitalization; all continued oral anticoagulant therapy after discharge. All patients (100%) were cured and discharged. No patients showed recurrence of AP or PE. CONCLUSION: PE is a rare but life-threatening complication of AP. However, once diagnosed, early treatment with anticoagulation or radiological interventional procedures is effective, and the prognosis is good. Core Tips: Pulmonary embolism (PE) is a rare but life-threatening complication of acute pancreatitis (AP). Its early diagnosis and timely anticoagulation or radiological intervention can reduce mortality. However, only nine cases have been reported in the English literature thus far, and they are all case reports. Our study is the first systematic analysis of patients with AP combined with PE with a review of the relevant literature. Our patients and those reported in the literature were discharged with good prognoses under treatment such as anticoagulation and vascular intervention. These cases remind clinicians that, in patients with AP, especially those with risk factors for venous thrombosis, it is necessary to monitor the D-dimer level dynamically. Clinicians should pay attention to AP patients' symptoms and related examinations to reduce the chance of a missed diagnosis or misdiagnosis of PE.

Qingjie Huagong decoction inhibits pancreatic acinar cell pyroptosis by regulating circHipk3/miR-193a-5p/NLRP3 pathway.

BACKGROUND: Safer and more effective drugs are needed for the treatment of acute pancreatitis (AP). Qingjie Huagong decoction (QJHGD) has been applied to treat AP for many years and has shown good clinical effects. However, the potential mechanism has not yet been determined. PURPOSE: To investigate the role and underlying mechanism of the effects of QJHGD on AP both in vitro and in vivo. METHODS: QJHGD was characterized by UHPLC-Q-Orbitrap-MS. The protective effect of QJHDG and the underlying mechanism were investigated in MPC-83 cells in vitro. A caerulein-induced AP model was established to evaluate the protective effect of QJHGD in mice. CCK-8 assays were used to detect cell viability. The contents of inflammatory mediators were determined by ELISA. Expression levels of circRNA, miRNA and mRNA were determined by qRT-PCR. Protein expression was determined using Western blot. Pancreatic tissues were assessed by hematoxylin and eosin staining as well as immunohistochemical and immunofluorescence analyses. Pull-down and luciferase activity assays were performed to determine the regulatory relationships of circHipk3, miR-193a-5p and NLRP3. RESULTS: Our results confirmed that mmu-miR-193a-5p was sponged by mmu-circHipk3, and NLRP3 was a target of miR-193a-5p. In vitro experiments showed that QJHGD enhanced MPC-83 cell viability by regulating circHipk3 sponging mir-193a-5 targeting NLRP3 and inhibiting pyroptosis-related factors. Finally, we showed that QJHGD ameliorated pancreatic tissue injury in AP mice via this pathway. CONCLUSION: This study demonstrate that QJHDG exerted its anti-AP effects via the circHipk3/miR-193a-5p/NLRP3 pathway, revealing a novel mechanism for the therapeutic effect of QJHDG on AP.

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.

Analysing pharmacodynamic interactions of traditional Chinese medicine in treating acute pancreatitis based on OPLS method.

Acute pancreatitis (AP) is a surgical abdominal disease for which the Dachengqi Decoction (DCQD) of traditional Chinese medicine (TCM) is widely used in China. This study aims to analyse the pharmacodynamic interactions and quantitative relationship of DCQD in the treatment of AP based on orthogonal partial least squares (OPLS) analysis. The experimental data show organic chemical components as candidate pharmacodynamic substances (PS) in the blood and include pharmacodynamic indicators (PIs). Taking each PI as the target and using OPLS method to construct three types of mathematical equations, including the mathematical relationship between the pharmacodynamic substances and each target pharmacodynamic indicator (PS-TPI); the mathematical relationship between the pharmacodynamic substances, the pharmacodynamics indicators and each target pharmacodynamic indicator (PS, PI-TPI); and the mathematical relationship between the pharmacodynamic indicators and each target pharmacodynamic indicator (PI-TPI). Through analysis, we find that the R2Y(cum) values and VIP values indicate that PS and PI are the follow-up factors of TPI; the coefficient value indicates that there is a quantitative relationship between the PS and the TPI; and there also is a quantitative relationship between PI and TPI. The results demonstrated that PS and other PIs are the important influencing factors of TPI, and that there are interactions and quantitative relationships among the PIs.

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.

Pyrazole derivative Z10 ameliorates acute pancreatitis by inhibiting the ERK/Ddt pathway.

Acute pancreatitis (AP) can lead to death; however, there is no specific treatment for AP. Screening of drugs for AP treatment is rarely performed. Compounds were screened in a primary pancreatic acinar cell and peritoneal macrophage coculture system. Compounds were used in vitro and in vivo. Compound targets were predicted and validated. Among the 18 nitrogen-containing heterocycles, Z10 was shown to decrease the cerulein plus lipopolysaccharide (CL)-induced secretion of both acinar digestive enzymes and macrophage cytokines. Z10 was also shown to ameliorate CL-induced or sodium taurocholate-induced AP in mice. Proteomics analysis and enzyme linked immunosorbent assay (ELISA) revealed that Z10 decreased the levels of D-dopachrome tautomerase (Ddt) within macrophages and those in the extracellular milieu under CL treatment. Z10 also decreased Ddt expression in AP mice. Moreover, exogenous Ddt induced cytokine and digestive enzyme secretion, which could be inhibited by Z10. Ddt knockdown inhibited CL-induced cytokine secretion. Medium from CL-treated macrophages induced the release of amylase by acinar cells, and Ddt knockdown medium decreased amylase secretion. The target of Z10 was predicted to be ERK2. Z10 increased the thermostability of ERK1/2 but not ERK1 K72A/ERK2 K52A. The docking poses of ERK1 and ERK2 with Z10 were similar. Z10 inhibited ERK1/2 phosphorylation, and Ddt levels and cytokines were regulated by ERK1/2 during AP. Additionally, Z10 could not further inhibit cytokines under ERK1/2 knockdown with CL. Thus, this study revealed that Z10-mediated ERK1/2 inhibition decreased Ddt expression and secretion by macrophages. Ddt inhibition decreased cytokine release and digestive enzyme secretion.

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.

Long term opioid use after burn injury: a retrospective cohort study.

BACKGROUND: Patients who have survive a burn injury might be at risk of opioid dependence after discharge. This study examined the use of opioids in patients who suffer burn injury and explored factors associated with persistent opioid use after hospital discharge. METHODS: This retrospective cohort study compared adults admitted with a burn injury from 2009 to 2019 with two matched comparison cohorts from the general population and adults with a diagnosis of acute pancreatitis. Pre-admission prescription opioid use was determined, and a multivariable negative binomial regression analysis used to explore post-discharge opioid use. RESULTS: A total of 7147 burn patients were matched with 6810 pancreatitis patients and with 28 184 individuals from the general population. Pre-admission opioid use was higher in the burn and pancreatitis cohorts (29% and 40%, respectively) compared with the general population (17%). Opioid use increased in both burn and pancreatitis cohorts after discharge (41% and 53%, respectively), although patients with pancreatitis were at even higher risk of increased opioid use in an adjusted analysis (incidence rate ratio 1.43). Female sex, lower socioeconomic status, ICU admission, pre-injury opioid use, and a history of excess alcohol use were all associated with an increase in opioid prescriptions after discharge. CONCLUSIONS: Opioid use is high in those admitted with a burn injury or acute pancreatitis when compared with the general population, increasing further after hospital discharge. Female sex and socioeconomic deprivation are among factors that make increased opioid use more likely, although this phenomenon seems even more pronounced in those with acute pancreatitis compared with burn injuries.

Adverse Impact of Sodium Bicarbonate Administration on Multiple Outcomes in Acute Pancreatitis Patients With Hyperlactatemia.

OBJECTIVE: Hyperlactatemia is likely to occur among patients with acute pancreatitis (AP). Sodium bicarbonate (SB) therapy could be applied to correct potential detrimental acidic disturbances, but the exact impact of SB treatment is unknown. This study aims to investigate the impact of SB on AP patients complicated with hyperlactatemia. METHODS: The study was conducted based on the database named Medical Information Mart for Intensive Care-IV (MIMIC-IV). Propensity matching (PSM) and inverse probability weighting (IPTW) were used to balance the baseline differences. Multivariate regression and marginal structural Cox models were performed to investigate the association between SB and multiple outcomes. RESULTS: Three hundred fifty-three AP patients with hyperlactatemia (initial serum lactate, >2.0 mmol/L) were extracted from the MIMIC-IV database. We found that SB treatment was significantly associated with worse multi-outcomes of AP patients with hyperlactatemia (in-hospital mortality: hazard ratio, 2.46; 95% confidence interval, 1.38-4.39; P < 0.01). Further analysis through marginal structural Cox models showed that SB had adverse impact on in-hospital prognosis of patients with severe lactic acidosis (pH < 7.15,lactate > 2.0 mmol/L). CONCLUSION: Sodium bicarbonate might not be an appropriate treatment for AP patients with hyperlactatemia (lactate > 2.0 mmol/L) or with severe lactic acidosis (pH < 7.15, lactate > 2.0 mmol/L).