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.

ß-Carotene Supplementation Improves Pancreas Function during Moderate Ethanol Consumption: Initial Characterization from a Morphological Overview.

Alcohol is believed to harm acinar cells, pancreatic ductal epithelium, and pancreatic stellate cells. After giving ethanol and/or ß-carotene to C57BL/6 mice, our goal was to evaluate their biochemistry, histology, and morpho-quantitative features. There were six groups of C57BL/6 mice: 1. Group C (control), 2. Group LA (low-dose alcohol), 3. Group MA (moderate-dose alcohol), 4. Group B (ß-carotene), 5. Group LA + B (low-dose alcohol combined with ß-carotene), and 6. Group MA + B (moderate-dose alcohol combined with ß-carotene). After the animals were euthanized on day 28, each specimen's pancreatic tissue was taken. Lipase, uric acid, and amylase were assessed using biochemical assessment. Furthermore, the examination of the pancreatic structure was conducted using Ammann's fibrosis scoring system. Finally, the morpho-quantitative characteristics of the pancreatic islets and acinar cells were determined. In the serum of the MA + B group, there were higher amounts of total amylase (825.953 ± 193.412 U/L) and lower amounts of lipase (47.139 ± 6.099 U/L) (p < 0.05). Furthermore, Ammann's fibrosis punctuation in the pancreas revealed significant variations between the groups (p < 0.001). Finally, the stereological analysis of pancreatic islets showed that the groups were different (p < 0.001). These findings suggest that antioxidant treatments might help decrease the negative effects of ethanol exposure in animal models.

Clean-DM1, a Korean Polyherbal Formula, Improves High Fat Diet-Induced Diabetic Symptoms in Mice by Regulating IRS/PI3K/AKT and AMPK Expressions in Pancreas and Liver Tissues.

OBJECTIVE: To investigate the effects of Clean-DM1 (C-DM1), a polyherbal formulation of Radix Scrophulariae, Radix Astragali, Rhizoma Atractylodis, and Radix Salviae Miltiorrhizae, on high-fat diet (HFD)-induced diabetes mice. METHODS: The information about active components of C-DM1 extract and molecular mechanism was obtained from network pharmacology analysis. Main compounds of C-DM1 extract by high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis were conducted for quality control. For in vivo study, mice were induced diabetes by HFD for 12 weeks. The mice in the normal group (Nor) were maintained with a regular diet and treated with saline by gavage. The HFD model mice were randomly divided into 3 groups, including a HFD diabetic model group, a C-DM1 extract-administered group (C-DM1, 500 mg/kg), and metformin-administered groups (Met, 500 mg/kg), 8 mice in each group. Food intake, body weight (BW), and fasting blood glucose (FBG) levels were recorded weekly for 4 weeks. After 4 weeks of treatment, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood glucose, low-density lipoprotein cholesterol (LDL-C) were determined using an automated clinical chemistry analyzer, and homeostatic model for assessing insulin resistance (HOMA-IR) levels and oral glucose tolerance test (OGTT) were detected. The histopathological changes of liver and pancreatic tissues were observed by hematoxylin-eosin staining. Insulin receptor substrate (IRS)/phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (AKT) and adenosine 5'-monophosphate-activated protein kinase (AMPK) expressions in liver and pancreas tissues were detected by Western blot analysis. RESULTS: HPLC-MS identified dihydroisotanshinone, dihydroisotanshinone I, cryptotanshinone, harpagoside, and atractyloside A in C-DM1 extract. The administration of C-DM1 extract significantly decreased body weight, calorie intake, and the levels of blood glucose and insulin in the diabetic mice (P<0.05 or P<0.01). The C-DM1 extract administration improved the impaired glucose tolerance and insulin resistance in the diabetic mice and significantly decreased the levels of LDL-C, ALT and AST (P<0.01). The C-DM1 extract inhibited the histopathological changes of fatty liver and hyperplasia of pancreatic islets in the diabetic mice. The C-DM1 extract significantly increased the phosphorylation of IRS, AKT, and AMPK and the expression of PI3K in pancreas and liver tissues (P<0.05 or P<0.01), which was consistent with the analysis results of network pharmacology. CONCLUSION: C-DM1 extract improved diabetes symptoms in long-term HFD-induced mice by regulation of IRS/PI3K/AKT and AMPK expressions in pancreas and liver tissues, suggesting that C-DM1 formulation may help prevent the progression of T2DM.

In vitro antioxidant capacity of Corryocactus brevistylus (sanky) and its effect on the pancreas morphology of alloxan-induced diabetic rats. / Capacidad antioxidante in vitro del Corryocactus brevistylus (sanky) y su efecto en la morfología del páncreas de ratas diabéticas inducidas con aloxano.

OBJECTIVE.: To determine the in vitro antioxidant capacity of Corryocactus brevistylus and its effect on glycemia and the pancreas of alloxan-induced diabetic rats. MATERIALS AND METHODS.: The antioxidant capacity of the hydroethanolic extract of sanky (HEES) was evaluated by assessing its ability to reduce 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric ion (FRAP). We used thirty adult rats, which were induced to diabetes with two doses of alloxan (80mg/kg). Rats were distributed into 5 groups (n=6), all groups received treatment by orogastric route for eight days. Group I received water, group II received metformin 14mg/kg and groups III, IV and V received sanky juice at 1.0; 4.0 and 16 mL/kg, respectively. Glycemia was evaluated by the rapid method (glucometer) (first and eighth day). After treatment, the animals were sacrificed and the pancreas was removed for histopathological study. RESULTS.: The antioxidant capacity of HEES by DPPH showed an IC50 of 0.77 mg/mL; the FRAP method showed a TEAC-FRAP of 22.31µg/mg. Glycemia decreased on the eighth day of treatment, with respect to the first day; a decrease in glycemia was also found in groups III-V, when compared to group I. Histologically, groups I-II presented severe atrophy and moderate necrosis of the islets of Langerhans; groups IV-V presented hypertrophy and mild multifocal necrosis at the islet level. CONCLUSIONS.: The extract of sanky showed antioxidant capacity in vitro and the juice exerts a hypoglycemic and protective effect on the pancreas.

OBJETIVO.: Determinar la capacidad antioxidante in vitro del Corryocactus brevistylus y su efecto sobre la glicemia y páncreas de ratas diabéticas inducidas con aloxano. MATERIALES Y MÉTODOS.: Se evaluó la capacidad antioxidante del extracto hidroetanólico de sanky (EHES) mediante la capacidad de reducir el 2,2-difenil-1-picrilhidracilo (DPPH) y la capacidad de reducir el ion férrico (FRAP). Se utilizaron 30 ratas adultas inducidas a diabetes con dos dosis de aloxano (80mg/kg), formándose cinco grupos (n=6), recibiendo los tratamientos vía orogástrica durante ocho días, el grupo I (agua), II (metformina 14mg/kg), grupos III-IV-V zumo de sanky a 1,0; 4,0 y 16 mL/kg, respectivamente. La glicemia fue evaluada por el método rápido (glucómetro) (primer y octavo día). Terminado el tratamiento los animales fueron sacrificados y se les extrajo el páncreas, para su estudio histopatológico. RESULTADOS.: La capacidad antioxidante del EHES mediante el DPPH, mostró un IC50 de 0,77 mg/mL, y por el método FRAP se observó el TEAC-FRAP de 22,31µg/mg. La glicemia disminuyó en el octavo día de tratamiento, respecto al primer día; también se observó disminución de la glicemia en los grupos III-V, respecto al grupo I. A nivel histológico los grupos I-II presentaron atrofia severa y necrosis moderada de los islotes de Langerhans; los grupos IV-V presentaron hipertrofia y necrosis leve multifocal a nivel del islote. CONCLUSIONES.: El extracto de sanky presenta capacidad antioxidante in vitro y el zumo ejerce un efecto hipoglicemiante y protector en páncreas.

Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels.

Pharmacological ascorbate (P-AscH-, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH- induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway. Both non-tumorigenic pancreatic ductal epithelial and PDAC cells display decreased clonogenic survival and increased doubling times after radiation treatment. In contrast, the addition of P-AscH- to radiation increases clonogenic survival and decreases the doubling time of non-tumorigenic epithelial cells but decreasing clonogenic survival and increasing the doubling time of PDAC cells. Results from the mitotic index and propidium iodide assays showed that while the P-AscH- treatments did not affect radiation-induced G2-checkpoint activation, it enhanced G2-accumulation. The addition of catalase reverses the increases in G2-accumulation, indicating a peroxide-mediated mechanism. In addition, P-AscH- treatment of PDAC cells suppresses radiation-induced accumulation of cyclin B1 protein levels. Both translational and post-translational pathways appear to regulate cyclin B1 protein levels after the combination treatment of PDAC cells with P-AscH- and radiation. The protein changes seen are reversed by the addition of catalase suggesting that hydrogen peroxide mediates P-AscH- induced radiation sensitization of PDAC cells by enhancing G2-accumulation and reducing cyclin B1 protein levels.

Exploring a novel composite method using non-contrast EUS enhanced microvascular imaging and cyst fluid analysis to differentiate pancreatic cystic lesions.

BACKGROUND AND AIMS: Differentiating pancreatic cystic lesions (PCLs) remains a diagnostic challenge. The use of high-definition imaging modalities which detect tumor microvasculature have been described in solid lesions. We aim to evaluate the usefulness of cystic microvasculature when used in combination with cyst fluid biochemistry to differentiate PCLs. METHODS: We retrospectively analyzed 110 consecutive patients with PCLs from 2 Italian Hospitals who underwent EUS with H-Flow and EUS fine needle aspiration to obtain cystic fluid. The accuracy of fluid biomarkers was evaluated against morphological features on radiology and EUS. Gold standard for diagnosis was surgical resection. A clinical and radiological follow up was applied in those patients who were not resected because not surgical indication and no signs of malignancy were shown. RESULTS: Of 110 patients, 65 were diagnosed with a mucinous cyst, 41 with a non-mucinous cyst, and 4 with an undetermined cyst. Fluid analysis alone yielded 76.7% sensitivity, 56.7% specificity, 77.8 positive predictive value (PPV), 55.3 negative predictive value (NPV) and 56% accuracy in diagnosing pancreatic cysts alone. Our composite method yielded 97.3% sensitivity, 77.1% specificity, 90.1% PPV, 93.1% NPV, 73.2% accuracy. CONCLUSIONS: This new composite could be applied to the holistic approach of combining cyst morphology, vascularity, and fluid analysis alongside endoscopist expertise.

Anti-inflammatory activity of curcumin in a model of L-arginine-induced acute pancreatitis in rats.

BACKGROUND: Acute pancreatitis (AP) is a pathology characterized by activated digestive enzymes to digest pancreatic tissue and inflammation. This study aimed to investigate the effect of curcumin, which has antioxidant and anti-inflammatory properties, on AP and its effectiveness at different doses. METHODS: Forty Sprague Dawley albino male rats, 12 weeks old, weighing 285-320 g, were used in the study. The rats were divided into control, curcumin, AP, low (100 mg/kg), and high (200mg/kg) dose curcumin groups. An experimental pancreatitis model was created with 5 g/kg L-arginine and samples (amylase, lipase, IL-1ß, IL-6, TNF-alpha, CRP, histopathological) were taken after 72 hours. RESULTS: There was no difference between the groups in terms of the weight of the rats (p=0.76). In the AP group, it was observed that the experimental pancreatitis model was successfully created after examination. Laboratory and histopathological examination results in the curcumin-administered groups were regressed compared to the AP group. The decrease in laboratory values was higher in the high-dose curcumin group than in the low-dose (p<0.001). CONCLUSION: Laboratory and histopathological changes occur in AP according to clinical severity. The antioxidant and anti-inflammatory effects of curcumin are known. In the light of this information and according to the results of our study, it has been shown that curcumin is effective in the treatment of AP, and the effect of curcumin increases with the dose increase. Curcumin is effective in treating AP. However, while high-dose curcumin was more effective in inflammatory response than low-dose, it showed similar histopathological results. KEY WORDS: Acute, Curcumin, Cytokines, Inflammation, Pancreatitis.

Stink bean (Parkia speciosa) empty pod: a potent natural antidiabetic agent for the prevention of pancreatic and hepatorenal dysfunction in high fat diet/streptozotocin-induced type 2 diabetes in rats.

The present study investigated the effect of polyphenol-rich extract of Parkia speciosa (PPS) against pancreatic and hepatorenal dysfunction in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetes. Diabetic rats were treated with PPS (100 and 400 mg/kg) and glibenclamide. The results revealed that diabetic rats displayed marked hyperglycaemia, hyperlipidaemia, hypoinsulinemia as well as alterations in serum renal and kidney function markers. Furthermore, diabetic rats showed significant increase in hepatorenal level of malonaldehyde as well as suppression of antioxidant enzyme activities. Whereas, diabetic rats that received PPS displayed marked attenuation in most of the aforementioned parameters compared to the untreated diabetic rats. Additionally, histological examination revealed restoration of histopathological alterations of the pancreas, liver, and kidney of PPS treated diabetic rats. In conclusion, the results demonstrated that PPS could decrease serum lipids and blood glucose level, enhance insulin level and hepatorenal antioxidant capacity, as well as ameliorate hepatorenal dysfunction in rats.

Antidiabetic and pancreas-protective potential of Parthenium Hysterophorous (Carrot grass) in Alloxan induced diabetic rabbits.

Parthenium hysterophorus has been used to cure cancer, fever, malaria, diarrhea, dysentery, and neurologic disorders. This study evaluates the anti-diabetic effects of methanolic extract of P. hysterophorus (MEPH) in alloxan-induced diabetic rabbits. Twenty-five rabbits were divided into 5groups (N=5). Group-I served as a negative control. Groups II to V were injected with freshly prepared alloxan solution 150 mg/kg intraperitoneally to induce diabetes. Group II till V received following treatments orally: Group II: Alloxan 150 mg/kg alone; group III: Alloxan + MEPH (50 mg/kg); group IV: Alloxan + MEPH (100 mg/kg); group V: Alloxan +Glucophage (62.5 mg/kg), respectively for 10 days. The body weight of all animals was recorded on the 1st, 4th, 7th and 10th days. Short-term (1st, 3rd, 5th and 7th hour) and long-term (4th, 7th and 10th day) hypoglycemic effects were also recorded. All animals were sacrificed on the 10th day to isolate the pancreas for histopathological examination. The results showed that MPEH reduced the blood glucose levels in all the groups of alloxan-induced diabetic rabbits. The histopathological studies depicted that 100 mg/kg of MEPH most effectively repaired alloxan-induced pancreatic damage. The study showed that the MPEH is useful for developing effective phytomedicine to treat diabetes mellitus.

Improved outcomes for borderline resectable adenocarcinoma of the pancreas after neoadjuvant chemotherapy in a community cancer center.

BACKGROUND: Borderline resectable adenocarcinoma of the pancreas involves the major vascular structures adjacent to the pancreas and has traditionally led to poor resection rates and survival. Newer chemotherapy regimens have demonstrated improved response and resection rates. We performed a retrospective review of borderline resectable pancreatic cancers who presented to a community cancer program to determine the effect of neoadjuvant chemotherapy to improve resection rates and overall survival. METHODS: Records of all patients diagnosed with adenocarcinoma of the pancreas from January 1, 2015 to December 31, 2019 were reviewed to determine stage at presentation, resectablility status, treatment methods, surgical resection and survival. Borderline resectable status was determined by preoperative imaging in agreement with published criteria from the National Comprehensive Cancer Network (NCCN) Guidelines 2.2021. Data was collected and analyzed by standard t-test. This study was approved by the institution's IRB. RESULTS: During this time period 322 patients were diagnosed with ductal adenocarcinoma of the pancreas of which 151 (47%) were unresectable, 31 (10%) were locally advanced, 70 (22%) were borderline resectable, and 69 (21%) were resectable at the time of presentation. 36 (51%) of the borderline resectable patients underwent neoadjuvant chemotherapy at our institution with either FOLFIRINOX or gemcitibine/nab-Paclitaxel regimens and served as the basis for this analysis. After neoadjuvant chemotherapy 24 (68%) of the borderline-resectable patients were deemed suitable for surgical exploration. At exploration, 15 (64%) were resected with 9 (60%) achieving margin-free resection on final pathology. The overall survival of those that underwent resection was increased by 19.6 months compared to those that did not undergo surgery (35.4 versus 15.8 mos, p < 0.01). Overall morbidity after resection was 46% (33% class 1 or 2, 13% class 3) with 0% mortality at 90 days. CONCLUSIONS: Use of neoadjuvant chemotherapy for borderline resectable adenocarcinoma of the pancreas results in improved resection rates and overall survival in resected patients. This management strategy for ductal adenocarcinoma of the pancreas is safe and feasible in a community-based cancer program.

Black pepper oil (Piper nigrum L.) mitigates dexamethasone induced pancreatic damage via modulation of oxidative and nitrosative stress.

Dexamethasone acts as an immunosuppressive drug and has been used recently in the management of specific coronavirus disease 2019 (COVID-19) cases; however, various adverse effects could limit its use. In this work, we studied the mitigation effects of black pepper oil (BP oil) on glycemic parameters, dyslipidemia, oxidative and nitrosative stress and pancreatic fibrosis in dexamethasone-treated rats. Animals were divided into five groups that were treated with vehicle, dexamethasone (10 mg/kg, SC) or black pepper oil (BP oil, 0.5 mL, or 1 mL/kg) or metformin (50 mg/kg) plus dexamethasone for 4 consecutive days. Serum insulin, blood glucose, total cholesterol, triglycerides, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were higher in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic nitric oxide, inducible nitric oxide synthase and malondialdehyde levels were increased in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic endothelial nitric oxide synthase and reduced glutathione were declined in the dexamethasone group vs the control group. They were increased in BP oil and metformin groups relative to the dexamethasone group. Moreover, the pancreatic islets diameter and collagen deposition were assessed and found to be higher in the dexamethasone group vs the control group. BP oil and metformin groups showed to regress this effect. In conclusion, BP oil may alleviate hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia and pancreatic structural derangements and fibrosis by suppressing oxidative stress, increasing endogenous antioxidant levels, modulating nitric oxide signaling, preventing pancreatic stellate cells transition and collagen deposition.

Metastasis to the Pancreas From Ductal Carcinoma In Situ of Breast Cancer: A Case Report and Review of Literature.

Background: The usual locations of metastatic breast neoplasms include the bones, the liver, the lung, and the brain. Breast cancer rarely metastasizes to the pancreas. However, pancreatic metastasis and primary pancreatic cancer are difficult to differentiate because of their similar clinical features and radiological characteristics. Case presentation: We report on a 49-year-old woman initially diagnosed with left breast ductal carcinoma in June 2008. The patient was admitted to the hospital with jaundice after 12 years. Computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed a mass in the pancreas head. Histopathology and immunohistochemistry showed ductal carcinoma originating from breast cancer. She underwent pancreatoduodenectomy to relieve jaundice. The patient is still alive with a favorable prognosis. Conclusions: In this paper, we mainly discuss the clinical characteristics, diagnostic methods, and surgical treatment of pancreatic metastasis. When a pancreatic lesion is detected with a history of breast cancer, the pancreatic metastasis likely originates from breast cancer.

Incredible affinity of Kattosh with PPAR-γ receptors attenuates STZ-induced pancreas and kidney lesions evidenced in chemicobiological interactions.

Since ancient times, plants have been used as green bioresources to ensure a healthier life by recovering from different diseases. Kattosh (Lasia spinosa L. Thwaites) is a local plant with various traditional uses, especially for arthritis, constipation and coughs. This research investigated the effect of Kattosh stem extract (LSES) on streptozotocin-induced damage to the pancreas, kidney, and liver using in vitro, in vivo and in silico methods. In vitro phytochemical, antioxidative and anti-inflammatory effects of LSES were accomplished by established methods followed by antidiabetic actions in in vivo randomized controlled intervention in STZ-induced animal models for four weeks. In an in silico study, LSES phytocompounds interacted with antidiabetic receptors of peroxisome proliferator-activated receptor-gamma (PPAR, PDB ID: 3G9E), AMP-activated protein kinase (AMPK, PDB ID: 4CFH) and α-amylase enzyme (PDB ID: 1PPI) to verify the in vivo results. In addition, LSES showed promising in vitro antioxidative and anti-inflammatory effects. In contrast, it showed a decrease in weekly blood glucose level, normalized lipid profile, ameliorated liver and cardiac markers, managed serum AST and ALT levels, and increased glucose tolerance ability in the animal model study. Restoration of pancreatic and kidney damage was reflected by improving histopathological images. In ligand-receptor interaction, ethyl α-d-glucopyranoside of Kattosh showed the highest affinity for the α-amylase enzyme, PPAR, and AMPK receptors. Results demonstrate that the affinity of Kattosh phytocompounds potentially attenuates pancreatic and kidney lesions and could be approached as an alternative antidiabetic source with further clarification.

Imaging of the Pancreas in New-Onset Diabetes: A Prospective Pilot Study.

INTRODUCTION: The aim of this study was to assess the feasibility of cross-sectional imaging for detection of pancreatic cancer (PDAC) in patients with new-onset hyperglycemia and diabetes (NOD). METHODS: We conducted a prospective pilot study from November 2018 to March 2020 within an integrated health system. Patients aged 50-85 years with newly elevated glycemic parameters without a history of diabetes were invited to complete a 3-phase contrast-enhanced computed tomography pancreas protocol scan while participating in the Prospective Study to Establish a NOD Cohort. Abnormal pancreatic findings, incidental extrapancreatic findings, and subsequent clinical evaluation were identified. Variability in clinical reporting between medical centers based on descriptors of pancreatic duct and parenchyma was assessed. RESULTS: A total of 130 of 147 participants (88.4%) consented to imaging; 93 scans were completed (before COVID-19 stay-at-home order). The median age was 62.4 years (interquartile range 56.3-68.8), 37.6% women; Hispanic (39.8%), White (29.0%), Black (14.0%), and Asian (13.3%). One (1.1%) case of PDAC (stage IV) was diagnosed, 12 of 93 participants (12.9%) had additional pancreatic findings: 5 fatty infiltration, 3 cysts, 2 atrophy, 1 divisum, and 1 calcification. There were 57 extrapancreatic findings among 52 of 93 (56%) unique patients; 12 of 57 (21.1%) prompted clinical evaluation with 2 additional malignancies diagnosed (nonsmall cell lung and renal oncocytoma). Reports from 1 participating medical center more frequently provided description of pancreatic parenchyma and ducts (92.9% vs 18.4%), P < 0.0001. DISCUSSION: High proportion of incidental findings and variability in clinical reports are challenges to be addressed for a successful NOD-based early detection strategy for PDAC.

Identification of an Immune-Related BAT Signature for Predicting Adjuvant Chemotherapy Response and Overall Survival in Patients with Resected Ductal Adenocarcinoma of the Pancreas.

BACKGROUND: Adjuvant chemotherapy (ACT) is widely accepted in patients with pancreatic ductal adenocarcinoma (PDAC) after surgery; however, effective models for predicting ACT response are scarce. Thus, the objective of this study was to develop a novel signature for predicting its response and overall survival (OS) in resected PDAC patients. METHODS: A total of 50 PDAC patients with the transcriptome expression profiles, information about chemotherapy, and relevant clinical data were retrieved from the Cancer Genome Atlas (TCGA), and twenty-nine patients with tissue specimens and clinical data from our hospital were included as a validation. A novel gene signature was developed using bioinformatic differentially expressed genes (DEGs) analysis, Lasso-penalized Cox regression, and multivariate Cox regression studies. RESULTS: Between chemotherapy-resistant and chemotherapy-sensitive cohorts, 569 DEGs were identified, with 490 upregulated and 79 downregulated genes mainly specialized in the regulation of peptide/protein/hormone secretion, calcium ion homeostasis, and T cell activation regulation in biological processes. After Lasso-penalized Cox and multivariate Cox regression analysis, BAT (BCHE, ADH1A, and TNS4) signature was established to predict ACT response and OS. Moreover, BAT signature was verified as an independent risk factor for ACT response (p = 0.042) and OS (median OS: 17.5 months vs. 34.8 months, p = 0.040) and significantly associated with immune infiltrations (p < 0.05). Then, this signature was further validated as the independent risk factor for recurrence-free survival (RFS) in PDAC patients receiving postoperative ACT (median RFS: 9.0 months vs. not reached, p = 0.014), and tumor-infiltrating CD4+ and CD8+ T cells were further validated to be significantly decreased in tissues with higher BAT signature scores (p = 0.015 and 0.021, respectively). CONCLUSION: The BAT signature is a novel formulated and independent risk factor for predicting ACT response and long-term survival in patients with resected PDAC. This signature could comprehensively reflect local immune-related response, tumor purity, potential biological behavior, and chemo drug susceptibility.

Epigenetic changes in inflammatory genes and the protective effect of cooked rhubarb on pancreatic tissue of rats with chronic alcohol exposure.

Chronic alcohol consumption, which is observed worldwide, can damage pancreatic tissue and promote pancreatitis. Rhubarb is a widely used traditional Chinese herbal medicine for treating pancreatitis in China. However, few pharmacological studies have investigated its epigenetic regulation. In this study, we investigated whether chronic exposure to alcohol can alter inflammatory gene expression and the epigenetic regulation effect of cooked rhubarb in the pancreatic tissue of rats. First, changes in inflammatory cytokine DNA methylation (IL-10, IL-1α, TNF-α, NF-κB and TGF-ß) were detected in pancreatic tissue of Sprague-Dawley rats with varying alcohol exposure times (4, 6, 8, or 12 weeks), and then with varying doses of cooked rhubarb treatment (3, 6, or 12 g/day). DNA methylation levels, related RNA concentrations and protein expression of specific inflammatory cytokines, and histopathological score were analysed in pancreatic tissue of Sprague-Dawley rats. The results showed that chronic alcohol exposure (8 weeks) reduced the level of IL-1α DNA methylation and increased its protein expression in acinar cells (P < 0.05). In the acinar cells, the level of IL-10 DNA methylation increased, resulting in a reduction of protein expression (P < 0.05). Simultaneously, chronic alcohol exposure increased the pathological damage to the pancreas (P < 0.05). Finally, cooked rhubarb treatment (3 g/kg/day) effectively alleviated these changes in pancreatic tissue from chronic alcohol exposure (P < 0.05). These results indicate that chronic exposure to alcohol leads to changes in DNA methylation and protein expression of inflammatory genes, and cooked rhubarb may have a protective effect on the pancreatic tissue of rats.

The impact of nutritional status on pancreatic cancer therapy.

INTRODUCTION: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive disease with poor outcomes. One of the reasons for the dismal prognosis resides in its impressive ability to alter the nutritional status of patients who develop malnutrition, cachexia, anorexia, and sarcopenia in most cases. The ideal way to measure such changes in PDAC patients, in order to readily identify them and avoid complications or discontinuations of treatment is a relatively unexplored area. In addition, most PDAC patients experience pancreatic exocrine insufficiency (PEI) that contributes to the complex puzzle of malnutrition and that can be treated with Pancreatic Enzyme Replacement Therapy (PERT). AREAS COVERED: We review current knowledge on the impact of nutritional status on both surgical and medical treatments for PDAC, reporting available data on the causes of malnutrition, characteristics, and advantages of different tools to investigate nutritional status and possible strategies to improve patient outcomes. EXPERT OPINION: All PDAC patients should receive a careful nutritional assessment at diagnosis, and this should be repeated alongside their treatment path. Screening tools and biochemical variables or scores are associated with prognosis, but bioimpedance vector analysis (BIVA) and radiological assessment of body composition seem more accurate in predicting clinical outcomes and postoperative complications.

Untargeted metabolomics analysis of the anti-diabetic effect of Red ginseng extract in Type 2 diabetes Mellitus rats based on UHPLC-MS/MS.

Red ginseng is a traditional Chinese herbal medicine that has long been used to treat diabetes, and its blood sugar-lowering activity has been confirmed. However, the mechanism of action of red ginseng on type 2 diabetes mellitus (T2DM) at the metabolic level is still unclear. The purpose of this study is to investigate the effect of red ginseng extract in the treatment of T2DM rats based on untargeted metabolomics. The rat model of T2DM was induced by a high-fat diet (HFD) combined with streptozotocin (STZ), and serum samples were collected after four weeks of treatment. The ultra-high-performance liquid chromatography coupled with Q Exactive HF-X Mass Spectrometer was used to analyze the level of metabolites in serum to evaluate the differences in metabolic levels between different groups. The results of biochemical analysis showed that red ginseng extract intervention significantly improved the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), serum glucose (GLU), and fasting insulin (FINS) after four weeks. Orthogonal partial least squares discriminant analysis was used to study the overall changes of rat metabolomics. After the intervention of red ginseng extract, 50 biomarkers showed a callback trend. Metabolic pathway enrichment analysis showed that the regulated pathways were D-arginine and D-ornithine metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, and tryptophan metabolism. Generally, the results demonstrated that red ginseng extract had beneficial effects on T2DM, which could be mediated via ameliorating the metabolic disorders.

Flavonoid constituents of Amomum tsao-ko Crevost et Lemarie and their antioxidant and antidiabetic effects in diabetic rats - in vitro and in vivo studies.

Amomum tsao-ko Crevost et Lemarie (A. tsao-ko) is a well-known dietary spice and traditional Chinese medicine. This study aimed to identify the flavonoids in A. tsao-ko and evaluate their antioxidant and antidiabetic activities in in vitro and in vivo studies. A. tsao-ko methanol extracts possessed a high flavonoid content (1.21 mg QE per g DW) and a total of 29 flavonoids were identified by employing UPLC-MS/MS. In vitro, A. tsao-ko demonstrated antioxidant activity (ORAC value of 34276.57 µM TE/100 g DW, IC50 of ABTS of 3.49 mg mL-1 and FRAP value of 207.42 µM Fe2+ per g DW) and α-amylase and α-glucosidase inhibitory ability with IC50 values of 14.23 and 1.76 mg mL-1, respectively. In vivo, type 2 diabetes mellitus (T2DM) models were induced by a combined high-fat diet (HFD) and streptozotocin (STZ) injection in rats. Treatment with the A. tsao-ko extract (100 mg freeze-dried powder per kg bw) for 6 weeks could significantly improve impaired glucose tolerance, decrease the levels of fasting blood glucose (FBG), insulin, and malondialdehyde (MDA), and increase the superoxide dismutase (SOD) level. Histopathology revealed that the A. tsao-ko extract preserved the architecture and function of the pancreas. In conclusion, the flavonoid composition of A. tsao-ko exhibits excellent antioxidant and antidiabetic activity in vitro and in vivo. A. tsao-ko could be a novel natural material and developed as a related functional food and medicine in T2DM management.

Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway.

Severe acute pancreatitis (SAP) is complicated by systemic inflammatory response syndrome and multiple organ dysfunction, the disease will eventually result in death in almost half of the case. The spleen, as the largest immune organ adjacent to the pancreas, is prone to damage in SAP, thereby aggravating the damage of other organs and increasing mortality. However, to date, the research on the mechanism and treatment of spleen injury caused by SAP is still in its infancy. Herein, we investigated the mechanism of spleen injury, and explored the application potential of tuftsin for relieving spleen damage in SAP mice. Firstly, SAP mice model was constructed via the retrograde infusion of 3.5 % sodium taurocholate into the biliopancreatic duct. Then, we proved that the up-regulation of Toll-like receptor 4 (TLR4) in spleen would lead to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. The splenic ROS and mitochondrial dysfunction could be improved by N-acetylcysteine (NAC) treatment or knocking out TLR4 in SAP mice. Meanwhile, we found that NAC treatment could also improve the autophagy of spleen tissue, suggesting that splenic ROS may affect impaired autophagy, causing the accumulation of damaged mitochondria, aggravating spleen damage. Furthermore, we verified the mechanism of spleen injury is caused by splenic ROS affecting PI3K/p-AKT/mTOR pathway-mediated autophagy. In addition, we detected the spleen injury caused by SAP could decrease the concentration of tuftsin in the serum of mice. Whereas, exogenous supplementation of tuftsin ameliorated the pathological damage, ROS accumulation, impaired autophagy, inflammation expression and apoptosis in damaged spleen. In summary, we verified the new mechanism of SAP-caused spleen damage that TLR4-induced ROS provoked mitophagy impairment and mitochondrial dysfunction in spleen via PI3K/p-AKT mTOR signaling, and the application potential of tuftsin in treating spleen injury, which might expand novel ideas and methods for the treatment of pancreatitis.