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PeerJ 2024Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and...
BACKGROUND
Andrographolide (Andro), an extract of (Burm.f.) Wall. ex Nees (Acanthaceae), possesses diverse biologically active properties. However, the precise mechanisms and effects of Andro on pancreatic cancer (PC) remain unclear.
METHODS
The cytotoxic potential of Andro and underlying mechanism towards PC cells was investigated through experiments and a xenograft mouse model. PC cells were first subjected to varying concentrations of Andro. The reactive oxygen species (ROS) was assessed using flow cytometry and DCFH-DA staining. The apoptosis rate was detected by flow cytometry. Additionally, western blot was applied to evaluate the expression levels of cleaved-caspase-3, DJ-1, LC3-I, LC3-II, and p62. To further elucidate the involvement of ROS accumulation and autophagy, we employed N-acetylcysteine as a scavenger of ROS and 3-Methyladenine as an inhibitor of autophagy.
RESULTS
Andro demonstrated potent anti-proliferative effects on PC cells and induced apoptosis, both and . The cytotoxicity of Andro on PC cells was counteracted by DJ-1 overexpression. The reduction in DJ-1 expression caused by Andro led to ROS accumulation, subsequently inhibiting the growth of PC cells. Furthermore, Andro stimulated cytoprotective autophagy, thus weakening the antitumor effect. Pharmacological blockade of autophagy further enhanced the antitumor efficacy of Andro.
CONCLUSION
Our study indicated that ROS accumulation induced by the DJ-1 reduction played a key role in Andro-mediated PC cell inhibition. Furthermore, the protective autophagy induced by the Andro in PC cells is a mechanism that needs to be addressed in future studies.
Topics: Reactive Oxygen Species; Diterpenes; Pancreatic Neoplasms; Autophagy; Protein Deglycase DJ-1; Animals; Humans; Mice; Cell Line, Tumor; Apoptosis; Xenograft Model Antitumor Assays; Mice, Nude
PubMed: 38952980
DOI: 10.7717/peerj.17619 -
MedComm Jul 2024cAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular...
CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA-binding motif protein 38.
cAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. cAMP responsive element binding protein 3 like 3 (CREB3L3), another member of bZIP family, was thought to be transcription factor (TF) to regulate hepatic metabolism. Nevertheless, except for being TFs, other function of bZIP family were poorly understood. In this study, we found CREB3 inhibited growth and metastasis of HCC in vitro and in vivo. RNA sequencing indicated CREB3 regulated AKT signaling to influence HCC progression. Mass spectrometry analysis revealed CREB3 interacted with insulin receptor (INSR). Mechanistically, CREB3 suppressed AKT phosphorylation by inhibiting the interaction of INSR with insulin receptor substrate 1 (IRS1). In our study, CREB3 was firstly proved to affect activation of substrates by interacting with tyrosine kinase receptor. Besides, CREB3 could act as a TF to transactivate RNA-binding motif protein 38 (RBM38) expression, leading to suppressed AKT phosphorylation. Rescue experiments further confirmed the independence between the two functional manners. In conclusion, CREB3 acted as a tumor suppressor in HCC, which inhibited AKT phosphorylation through independently interfering interaction of INSR with IRS1, and transcriptionally activating RBM38.
PubMed: 38952575
DOI: 10.1002/mco2.633 -
Frontiers in Endocrinology 2024We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was...
We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was performed at the age of three weeks. Later, histological analysis of her pancreas in a research setting revealed a focal form of CHI. Genetic testing was not available at that time. The patient developed pancreatic exocrine deficiency and insulin-dependent diabetes at the age of 9 years. In 2016, a genetic test revealed a missense heterozygous variant in the ABCC8 gene inherited from her father and classified as having a recessive inheritance. The geneticist concluded that the risk of CHI for her offspring would be low (1/600), making pregnancy favourable. As there was no consanguinity in the family, testing the future father was deemed unnecessary (carrier frequency 1/150 in the general population). The pregnancy occurred spontaneously in 2020 and at a gestational age of 28 weeks, the mother went into premature labour. An emergency C-section was performed in April 2021 resulting in the birth of bichorial bi-amniotic male twins. Following birth, both newborns experienced persistent severe hypoglycaemia which required glucagon treatment and intravenous glucose infusion initially, followed by Diazoxide from day 51 after birth, without satisfactory response. Continuous intravenous Octreotide treatment was introduced on day 72. Due to the recurrence of hypoglycaemia episodes despite reaching maximum doses of Octreotide, from day 92 the treatment was switched to Pasireotide. Genetic tests revealed the same genotypes for both infants: the exon 39 missense variant (c.4716C>A; p.Ser1572Arg) inherited from their mother and a truncating variant in exon 28 (c.3550del; p.Val1184*), inherited from their asymptomatic father. As a result of inheriting two recessive variants of the ABCC8 gene, the children were diagnosed with a diffuse form of CHI, consistent with the diazoxide-unresponsive presentation. This situation is very rare outside consanguinity. This case emphasises the significance of genetic counselling for individuals with a history of rare diseases outside the context of consanguinity, as there is a potential risk of recurrence. Prenatal diagnosis can lead to better outcomes for affected neonates, as well as help families make informed decisions about future pregnancies.
Topics: Humans; Female; Congenital Hyperinsulinism; Pregnancy; Adult; Infant, Newborn; Sulfonylurea Receptors; Male; Twins, Dizygotic
PubMed: 38952388
DOI: 10.3389/fendo.2024.1408003 -
Frontiers in Endocrinology 2024To develop and validate radiomics models utilizing endoscopic ultrasonography (EUS) images to distinguish insulinomas from non-functional pancreatic neuroendocrine...
Endoscopic ultrasonography-based intratumoral and peritumoral machine learning radiomics analyses for distinguishing insulinomas from non-functional pancreatic neuroendocrine tumors.
OBJECTIVES
To develop and validate radiomics models utilizing endoscopic ultrasonography (EUS) images to distinguish insulinomas from non-functional pancreatic neuroendocrine tumors (NF-PNETs).
METHODS
A total of 106 patients, comprising 61 with insulinomas and 45 with NF-PNETs, were included in this study. The patients were randomly assigned to either the training or test cohort. Radiomics features were extracted from both the intratumoral and peritumoral regions, respectively. Six machine learning algorithms were utilized to train intratumoral prediction models, using only the nonzero coefficient features. The researchers identified the most effective intratumoral radiomics model and subsequently employed it to develop peritumoral and combined radiomics models. Finally, a predictive nomogram for insulinomas was constructed and assessed.
RESULTS
A total of 107 radiomics features were extracted based on EUS, and only features with nonzero coefficients were retained. Among the six intratumoral radiomics models, the light gradient boosting machine (LightGBM) model demonstrated superior performance. Furthermore, a peritumoral radiomics model was established and evaluated. The combined model, integrating both the intratumoral and peritumoral radiomics features, exhibited a comparable performance in the training cohort (AUC=0.876) and achieved the highest accuracy in predicting outcomes in the test cohorts (AUC=0.835). The Delong test, calibration curves, and decision curve analysis (DCA) were employed to validate these findings. Insulinomas exhibited a significantly smaller diameter compared to NF-PNETs. Finally, the nomogram, incorporating diameter and radiomics signature, was constructed and assessed, which owned superior performance in both the training (AUC=0.929) and test (AUC=0.913) cohorts.
CONCLUSION
A novel and impactful radiomics model and nomogram were developed and validated for the accurate differentiation of NF-PNETs and insulinomas utilizing EUS images.
Topics: Humans; Machine Learning; Pancreatic Neoplasms; Endosonography; Female; Male; Middle Aged; Insulinoma; Adult; Neuroendocrine Tumors; Diagnosis, Differential; Aged; Nomograms; Radiomics
PubMed: 38952387
DOI: 10.3389/fendo.2024.1383814 -
Scientific Reports Jul 2024The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This...
The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients' immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.
Topics: Humans; Carcinoma, Pancreatic Ductal; Killer Cells, Natural; Prognosis; Pancreatic Neoplasms; Biomarkers, Tumor; Single-Cell Analysis; Female; Male; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Tumor Microenvironment; Middle Aged; Aged; Gene Expression Profiling
PubMed: 38951569
DOI: 10.1038/s41598-024-65917-1 -
Plant Foods For Human Nutrition... Jul 2024Chronic diseases like cancer and diabetes are the major public health concerns of India and worldwide. Nowadays, plant-derived products are in great demand for the...
Chronic diseases like cancer and diabetes are the major public health concerns of India and worldwide. Nowadays, plant-derived products are in great demand for the treatment of these diseases. Pumpkin seeds are traditionally implicated for their pharmacological properties, as exemplified by benign prostatic hyperplasia. Earlier, pumpkin seed proteins were extracted by the Osborne method, and their functional and nutritional qualities were evaluated. Here, the aim is to assess in vitro, the anticancer and antidiabetic properties of seed protein fractions. HepG2, MDA-MB-231, and MCF-7 cell lines were treated with water-soluble (WF) and alkali-soluble fractions (AF) to assess cytotoxicity, while pancreatic β-cells and insulin resistance (IR) - HepG2 cell lines were treated with WF to evaluate the antidiabetic potential. WF and AF showed cytotoxic effects towards HepG2 and MDA-MB-231 cell lines, suggesting apoptosis-mediated anticancerous activity. WF potentiates glucose-stimulated insulin secretion in pancreatic β-cells, in a dose-dependent manner. In IR-HepG2 cell line studies, control, metformin, and WF-treated groups showed uptake of glucose, when compared to the diabetic group, which is well-correlated with the upregulated expressions of GLUT2 and GLUT4 transporters in these groups. These results indicate that proteins from WF and AF may have anticancerous and antidiabetic properties and thus have the potential to utilize pumpkin proteins in the management of cancer and diabetes.
PubMed: 38951376
DOI: 10.1007/s11130-024-01205-7 -
Journal of Cancer Research and Clinical... Jul 2024In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy.
PATIENTS AND METHODS
The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11.
RESULTS
The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed.
CONCLUSION
The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
Topics: Humans; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Male; Fluorouracil; Female; Middle Aged; Leucovorin; Aged; Oxaliplatin; Irinotecan; Adult; Camptothecin; Progression-Free Survival; Cross-Over Studies
PubMed: 38951245
DOI: 10.1007/s00432-024-05827-x -
Zhonghua Nei Ke Za Zhi Jul 2024
Review
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Intestinal Neoplasms; Stomach Neoplasms
PubMed: 38951086
DOI: 10.3760/cma.j.cn112138-20231229-00415 -
Endoscopy Dec 2024
Topics: Humans; Pancreatic Ducts; Drainage; Endosonography; Ultrasonography, Interventional; Male; Stents; Middle Aged; Female
PubMed: 38950886
DOI: 10.1055/a-2334-0926 -
Acta Medica Portuguesa Jul 2024
Topics: Humans; Pancreatic Neoplasms; Pancreatectomy; Time Factors; Operative Time
PubMed: 38950613
DOI: 10.20344/amp.21621