Baicalin protects against hepatocyte injury caused by aflatoxin B1 via the TP53-related ferroptosis Pathway.

OBJECTIVE: Baicalin has antioxidative, antiviral, and anti-inflammatory properties. However, its ability to alleviate oxidative stress (OS) and DNA damage in liver cells exposed to aflatoxin B1 (AFB1), a highly hepatotoxic compound, remains uncertain. In this study, the protective effects of baicalin on AFB1-induced hepatocyte injury and the mechanisms underlying those effects were investigated. METHODS: Stable cell lines expressing CYP3A4 were established using lentiviral vectors to assess oxidative stress levels by conducting assays to determine the content of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Additionally, DNA damage was evaluated by 8-hydroxy-2-deoxyguanosine (8-OHdG) and comet assays. Transcriptome sequencing, molecular docking, and in vitro experiments were conducted to determine the mechanisms underlying the effects of baicalin on AFB1-induced hepatocyte injury. In vivo, a rat model of hepatocyte injury induced by AFB1 was used to evaluate the effects of baicalin. RESULTS: In vitro, baicalin significantly attenuated AFB1-induced injury caused due to OS, as determined by a decrease in ROS, MDA, and SOD levels. Baicalin also considerably decreased AFB1-induced DNA damage in hepatocytes. This protective effect of baicalin was found to be closely associated with the TP53-mediated ferroptosis pathway. To elaborate, baicalin physically interacts with P53, leading to the suppression of the expression of GPX4 and SLC7A11, which in turn inhibits ferroptosis. In vivo findings showed that baicalin decreased DNA damage and ferroptosis in AFB1-treated rat liver tissues, as determined by a decrease in the expression of γ-H2AX and an increase in GPX4 and SLC7A11 levels. Overexpression of TP53 weakened the protective effects of baicalin. CONCLUSIONS: Baicalin can alleviate AFB1-induced OS and DNA damage in liver cells via the TP53-mediated ferroptosis pathway. In this study, a theoretical foundation was established for the use of baicalin in protecting the liver from the toxic effects of AFB1.

Rising sun or strangled in the cradle？A narrative review of near-infrared fluorescence imaging-guided surgery for pancreatic tumors.

Near-infrared fluorescence (NIRF)-guided surgical navigation has become a promising and effective detection method in pancreatic tumor surgery. The imaging technique has gradually transitioned from the NIR-I region to the NIR-II region. Real-time assessment of the tumor boundary and determination of the ideal resection plane are essential for preserving the pancreatic parenchyma and its secretory functions. However, since the pancreatic parenchyma has a less rich blood supply than the liver, the application of contrast agents in pancreatic tumor surgery is still in its infancy. The application of indocyanine green (ICG) and methylene blue (MB) in intraoperative NIRF imaging of pancreatic tumors has become more mature, but due to the characteristics of non-specific imaging, the imaging efficiency and depth need to be improved. Many tumor-specific imaging agents have been designed, but most of them have not gone past animal trials because of their high development and imaging costs, biotoxicity, and other limitations. In this article, we review recent reports of ICG, MB and newly developed contrast agents and imaging devices. We focus on the current status and new developments in the application of these contrast agents and summarize the current clinical and preclinical studies on specific contrast agents. We synthesize relevant reports to discuss the difficulties and prospects of the application of fluorescent imaging agents in pancreatic tumors. We hope that reviewing previous studies and the current progress on contrast imaging technology will provide new perspectives for its future application and development in pancreatic tumor surgery, which should translate into better patient prognoses. The manuscript was written according to the Scale for the Assessment of Narrative Review Articles (SANRA).

JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5 year survival rate less than 12%. This malignancy is closely related to the unique tumor microenvironment (TME), which is characterized by a hypovascular and hyperdense extracellular matrix, making it difficult for drugs to permeate the tumor center. Near-infrared fluorescence (NIRF) imaging, which has high sensitivity and resolution, may improve the survival rate of PDAC patients. In this study, we first used JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazine-1-yl] diazene-1-ium-1,2-diolate) to specifically dilate blood vessels within the TME of PDAC patients and subsequently injected IR820-PEG-MNPs (IPM NPs) to diagnose and treat orthotopic PDAC. We found that JS-K promoted the accumulation of IPM NPs in orthotopic Pan02 tumor-bearing mice and was able to increase the tumor signal-to-background ratio (SBR) in the orthotopic PDAC area by 41.5%. In addition, surgical navigation in orthotopic Pan02 tumor-bearing mice and complete tumor resection based on fluorescence imaging were achieved with a detection sensitivity of 81.0%. Moreover, we verified the feasibility of the combination of laparoscopy and photothermal ablation (PTA) for the treatment of PDAC. Finally, we demonstrated that IPM NPs had greater affinity for human PDAC tissues than for normal pancreatic tissues ex vivo, preliminarily highlighting the potential for clinical translation of these NPs. In conclusion, we developed and validated a novel sequential delivery strategy that promotes the accumulation of nanoagents in the tumor area and can be used for the diagnosis and treatment of PDAC.

Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection.

Objective: To explore the frequency distribution of KRAS mutant subtypes in patients with resectable PDAC in China and then evaluate the prognostic value of different KRAS subtypes in patients with PDAC undergoing radical resection. Methods: The clinicopathological data and gene test reports of 227 patients undergoing PDAC radical surgery at Hunan Provincial People's Hospital from 1 January 2016 to 1 January 1 2020 were retrospectively evaluated. There were 118 men (52%) and 109 women (48%). The mean age was 58.8 ± 10.3 years. After univariate analysis of the clinicopathological factors (sex, age, presence or absence of underlying disease, location of the primary tumour, tumour TNM stage, T stage, N stage, presence or absence of vascular invasion, presence or absence of nerve invasion, surgical margin, KRAS mutation subtype), variables with P < 0.1 were included in the multivariate Cox regression model analysis, and the log-rank sum test and Kaplan-Meier curves were used to assess the correlation of the KRAS mutation subtype with the overall survival time. Results: KRAS mutations were detected in 184 of 227 patients (81.1%) (G12D: 66; G12V: 65; G12R: 27; Q61:26) and were not detected in 43 patients (18.9%). KRAS mutations were associated with tumour differentiation (P = 0.001), TNM stage (P = 0.013), and T stage (P < 0.001). Multivariate Cox regression model analysis showed that N stage, surgical margin, tumour differentiation, and KRAS-G12D mutation were independent prognostic factors for DFS and OS. Patients with the KRAS-G12D subtype had shorter OS with a median OS of 12 months (HR: 0.55, CI: 0.39-0.77, P < 0.001), and patients with KRAS wild-type had longer OS with a median OS of 19 months (HR: 0.57, CI: 0.42-0.76, P < 0.001). Conclusion: KRAS wild-type individuals are more prevalent in the Chinese population than in European or American populations. Patients undergoing surgery had a reduced percentage of tumors with KRAS-G12D. When determining the prognosis of individuals with radically resected PDAC, reference markers for KRAS mutation subtypes can be employed.

KRAS as a Key Oncogene in the Clinical Precision Diagnosis and Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors, with a 5-year survival rate of less than 10%. At present, the comprehensive treatment based on surgery, radiotherapy and chemotherapy has encountered a bottleneck, and targeted immunotherapy turns to be the direction of future development. About 90% of PDAC patients have KRAS mutations, and KRAS has been widely used in the diagnosis, treatment, and prognosis of PDAC in recent years. With the development of liquid biopsy and gene testing, KRAS is expected to become a new biomarker to assist the stratification and prognosis of PDAC patients. An increasing number of small molecule inhibitors acting on the KRAS pathway are being developed and put into the clinic, providing more options for PDAC patients.