Therapeutic properties of Isoliquiritigenin with molecular modeling studies: Investigation of anti-pancreatic acinar cell tumor and as HMG-CoA reductase inhibitor for treatment of hypercholesterolemia

IntroductionIsoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have an anti-tumor activity in vitro and in vivo. HMG-CoA reductase inhibitors, called statins, are used to reduce the risk of heart disease by lowering blood cholesterol levels.Material and methodsHMG-CoA Reductase activity according to the method described by Takahashi S. et al. The structure of human HMG-COA reductase in the resolution of 2.22 Å with X-RAY diffraction method (PDB ID: 1HWK) was obtained from the PDB database.ResultsIn our study, inhibition result of Isoliquiritigenin on HMG-CoA reductase showed lower value IC50 = 193.77±14.85 µg / mL. For a better understanding of biological activities and interactions, the molecular docking study was accomplished. The results of molecular docking revealed that isoliquiritigenin with a docking score of -6.740 has a strong binding affinity to the HMG-COA reductase. Therefore, this compound could be considered as a potential inhibitor for the enzyme. Also, the properties of Isoliquiritigenin against common human pancreatic acinar cell tumor cell lines i.e. 266-6, TGP49, and TGP47 were evaluated.ConclusionsThe treated cells with Isoliquiritigenin were assessed by MTT assay for 48h about the cytotoxicity and anti-human pancreatic acinar cell tumor properties on normal (HUVEC) and human pancreatic acinar cell tumor cell lines i.e. 266-6, TGP49, and TGP47. The IC50 of Isoliquiritigenin were 262, 389, and 211 µg/mL against 266-6, TGP49, and TGP47 cell lines, respectively.

Survival Outcome and Prognostic Factors for Pancreatic Acinar Cell Carcinoma: Retrospective Analysis from the German Cancer Registry Group

Background: Pancreatic acinar cell carcinoma (PACC) is a distinct type of pancreatic cancer with low prevalence. We aimed to analyze prognostic factors and survival outcome for PACC in comparison to pancreatic ductal adenocarcinoma (PDAC), based on data from the German Cancer Registry Group. Methods: Patients with PACC and PDAC were extracted from pooled data of the German clinical cancer registries (years 2000 to 2019). The distribution of demographic parameters, tumor stage and therapy modes were compared between PACC and PDAC. The Kaplan–Meier method and Cox regression analysis were used to delineate prognostic factors for PACC. Propensity score matching was used to compare survival between PACC and PDAC. Results: There were 233 (0.44%) patients with PACC out of 52,518 patients with pancreatic malignancy. Compared to PDAC, patients with PACC were younger (median age 66 versus 70, respectively, p < 0.001) and the percentage of males was higher (66.1% versus 53.3%, respectively, p < 0.001). More patients were resected with PACC than with PDAC (56.2% versus 38.9%, respectively, p < 0.001). The estimated overall median survival in PACC was 22 months (95% confidence interval 15 to 27), compared to 12 months (95% confidence interval 10 to 13) in the matched PDAC cohort (p < 0.001). Surgical resection was the strongest positive prognostic factor for PACC after adjusting for sex, age, and distant metastases (hazard ratio 0.34, 95% confidence interval 0.22 to 0.51, p < 0.001). There was no survival benefit for adjuvant therapy in PACC. Conclusions: PACC has overall better prognosis than PDAC. Surgical resection is the best therapeutic strategy for PACC and should be advocated even in advanced tumor stages.

CaMK II Inhibition Attenuates ROS Dependent Necroptosis in Acinar Cells and Protects against Acute Pancreatitis in Mice

As a calcium-regulated protein, CaMK II is closely related to cell death, and it participates in the development of pathological processes such as reperfusion injury, myocardial infarction, and oligodendrocyte death. The function of CaMK II activation in acute pancreatitis (AP) remains unclear. In our study, we confirmed that the expression of p-CaMK II was increased significantly and consistently in injured pancreatic tissues after caerulein-induced AP. Then, we found that KN93, an inhibitor of CaMK II, could mitigate the histopathological manifestations in pancreatic tissues, reduce serum levels of enzymology, and decrease oxidative stress products. Accordingly, we elucidated the effect of KN93 in vitro and found that KN93 had a protective effect on the pancreatic acinar cell necroptosis pathway by inhibiting the production of ROS and decreasing the expression of RIP3 and p-MLKL. In addition, we identified the protective effect of KN93 on AP through another mouse model induced by pancreatic duct ligation (PDL). Together, these data demonstrated that CaMK II participates in the development of AP and that inhibiting CaMK II activation could protect against AP by reducing acinar cell necroptosis, which may provide a new idea target for the prevention and treatment of AP in the clinic.

Carboxypeptidase A1 (CPA1) immunohistochemistry is highly sensitive and specific for acinar cell carcinoma (ACC) of the pancreas

Introduction/Objective Introduction: Carboxypeptidase A1 (CPA1) is a zinc metalloprotease which is produced in pancreatic acinar cells and plays a role in cleaving C-terminal branched-chain and aromatic amino acids from dietary proteins. This study assessed the utility of immunohistochemical CPA1 staining for diagnosing pancreatic acinar cell carcinoma. Methods/Case Report Methods: A total of 15,680 tumor samples from 132 different tumor types and subtypes as well as 8 samples each of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results (if a Case Study enter NA) Results: CPA1 was strongly expressed in acinar cells of all normal pancreas samples but not in any other normal tissues. CPA1 immunostaining was detected in 100% of 11 pancreatic acinar cell carcinomas and one mixed acinar endocrine carcinoma (MAEC), but absent in 449 pancreatic ductal adenocarcinomas, 75 adenocarcinomas of the ampulla of Vater, and 11,739 other evaluable cancers from 128 different tumor entities. A weak to moderate diffuse staining of epithelial and stromal cells of cancer tissues immediately adjacent to non-neoplastic pancreatic acinar cells often occurred and was considered to be caused by diffusion of the highly abundant CPA1 from normal acinar cells that may have suffered some autolytic cell damage. Conclusion Our data show that CPA1 is a highly sensitive and largely specific marker for normal and neoplastic pancreatic acinar cells. CPA1 immunohistochemistry greatly facilitates the otherwise often difficult diagnosis of pancreatic acinar cell carcinoma.