Hspb1 protects against severe acute pancreatitis by attenuating apoptosis and ferroptosis via interacting with Anxa2 to restore the antioxidative activity of Prdx1.

Acute pancreatitis (AP) is a common abdominal disease that typically resolves on its own, but the mortality rate dramatically increases when it progresses to severe acute pancreatitis (SAP). In this study, we investigated the molecular mechanism underlying the development of SAP from AP. We utilized two SAP models induced by pancreatic duct ligation and caerulein administration. Transcriptomic and proteomic analyses were subsequently performed to determine the mRNA and protein expression profiles of pancreatic samples from SAP and AP model and normal mice. To explore the role of Hspb1 in SAP, we used Hspb1 knockout (KO) mice, a genetically engineered chronic pancreatitis strain (T7D23A), Anxa2 KO mice, and acinar cell-specific Prdx1 knockout mice. Additionally, various in vivo and in vitro assays were performed to elucidate the molecular events and direct targets of Hspb1 in acinar cells. We found that Hspb1 expression was upregulated in AP samples but significantly reduced in acinar cells from SAP samples. KO or inhibition of Hspb1 worsened AP, while AAV8-Hspb1 administration mitigated the severity of SAP and reduced remote organ damage in mice. Furthermore, AAV8-Hspb1 treatment prevented the development of chronic pancreatitis. We found that KO or inhibition of Hspb1 promoted acinar cell death through apoptosis and ferroptosis but not necroptosis or autophagy by increasing reactive oxygen species (ROS) and lipid ROS levels. Mechanistically, Hspb1 directly interacted with Anxa2 to decrease its aggregation and phosphorylation, interact with the crucial antioxidant enzyme Prdx1, and maintain its antioxidative activity by decreasing Thr-90 phosphorylation. Notably, the overexpression of Hspb1 did not have a protective effect on acinar-specific Prdx1 knockout mice. In summary, our findings shed light on the role of Hspb1 in acinar cells. We showed that targeting Hspb1/Anxa2/Prdx1 could serve as a potential therapeutic strategy for SAP.

Chronic exposure to BDE-47 aggravates acute pancreatitis and chronic pancreatitis by promoting acinar cell apoptosis and inflammation.

The effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a persistent environmental pollutant commonly used as a flame retardant in various consumer products, on pancreatitis has not been clearly elucidated, although it has been reported to be toxic to the liver, nervous system, and reproductive system. Acute pancreatitis (AP) and chronic pancreatitis (CP) models were induced in this study by intraperitoneal injection of caerulein. The aim was to investigate the impact of BDE-47 on pancreatitis by exposing the animals to acute (1 week) or chronic (8 weeks) doses of BDE-47 (30 mg/kg in the low-concentration group and 100 mg/kg in the high-concentration group). Additionally, BDE-47 was utilized to stimulate mouse bone marrow-derived macrophages, pancreatic primary stellate cells, and acinar cells in order to investigate the impact of BDE-47 on pancreatitis. In vivo experiments conducted on mice revealed that chronic exposure to BDE-47, rather than acute exposure, exacerbated the histopathological damage of AP and CP, leading to elevated fibrosis in pancreatic tissue and increased infiltration of inflammatory cells in the pancreas. In vitro experiments showed that BDE-47 can promote the expression of the inflammatory cytokines Tnf-α and Il-6 in M1 macrophages, as well as promote acinar cell apoptosis through the activation of the PERK and JNK pathways via endoplasmic reticulum stress. The findings of this study imply chronic exposure to BDE-47 may exacerbate the progression of both AP and CP by inducing acinar cell apoptosis and dysregulating inflammatory responses.

Kinesin family member 11 promotes progression of hepatocellular carcinoma via the OCT4 pathway.

Hepatocellular carcinoma (HCC) is the tumor with the second highest mortality rate worldwide. Recent research data show that KIF11, a member of the kinesin family (KIF), plays an important role in the progression of various tumors. However, its expression and molecular mechanism in HCC remain elusive. Here, we evaluated the potential role of KIF11 in HCC. The effect of KIF11 was evaluated using the hepatocellular carcinoma cell lines, LM3 and Huh7, after genetic or pharmacological treatment. Evaluating the role of KIF11 in the xenograft animal models using its specific inhibitor. The role of KIF11 was systematically evaluated using specimens obtained from the aforementioned animal and cell models after various in vivo and in vitro experiments. The clinicopathological analysis showed that KIF11 was expressed at high levels in patients with hepatocellular carcinoma. Cell experiments in vitro showed that KIF11 deficiency significantly slowed the proliferation of liver tumor cells. And in the experiment using liver cancer cells overexpressing OCT4, overexpression of OCT4 substantially increased the proliferation of tumor cells compared with tumor cells with KIF11 knockdown alone. Both in vitro cell experiment and in vivo xenotransplantation tumor experiment showed that monastrol, an inhibitor of KIF11, could effectively delay the proliferation and migration of tumor cells. Based on these results, KIF11 is expressed at high levels in hepatocellular carcinoma and promotes tumor proliferation in an OCT4-dependent manner. KIF11 may become a therapeutic target for hepatocellular carcinoma, and its inhibitor monastrol may become a clinical antitumor drug.

A bioinformatics approach to identify a disulfidptosis-related gene signature for prognostic implication in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a type of cancer that arises from the glandular epithelial cells that produce mucus in the colon. COAD is influenced by various factors, including genetics, environment and lifestyle. The outcome of COAD is determined by the tumor stage, location, molecular characteristics and treatment. Disulfidptosis is a new mode of cell death that may affect cancer development. We discovered genes associated with disulfidptosis in colon adenocarcinoma and proposed them as novel biomarkers and therapeutic targets for COAD. We analyzed the mRNA expression data and clinical information of COAD patients from The Cancer Genome Atlas (TCGA) database and Xena databases, extracted disulfidptosis-related genes from the latest reports on disulfidptosis. We used machine learning to select key features and build a signature and validated the risk model using data from the Gene Expression Omnibus (GEO) database and Human Protein Atlas (HPA). We also explored the potential biological functions and therapeutic implications of the disulfidptosis-related genes using CIBERSORTx and GDSC2 databases. We identified four disulfidptosis-related genes: TRIP6, OXSM, MYH3 and MYH4. These genes predicted COAD patient survival and modulated the tumor microenvironment, drug sensitivity and immune microenvironment. Our study reveals the importance of disulfidptosis-related genes for COAD prognosis and therapy. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings may facilitate personalized cancer treatment.

Integrative proteomics, phosphoproteomics and acetylation proteomics analyses of acute pancreatitis in rats.

Acute pancreatitis (AP) is a common acute abdominalgia of the digestive tract. When the disease progresses to severe acute pancreatitis (SAP), the complications and mortality rate greatly increase. Determining the key factors and pathways underlying AP and SAP will help elucidate the pathological processes involved in disease progression and will be beneficial for identifying potential therapeutic targets. We conducted an integrative proteomics, phosphoproteomics and acetylation proteomics analysis of pancreas samples collected from normal, AP and SAP rat models. We identified 9582 proteins, 3130 phosphorylated modified proteins, and 1677 acetylated modified proteins across all samples. The differentiated expression proteins and KEGG pathway analysis suggested the pronounced enrichment of key pathways based on the following group comparisons: AP versus normal, SAP versus normal, and SAP versus AP. Integrative proteomics and phosphoproteomics analyses revealed 985 jointly detected proteins in the comparison of AP and normal samples, 911 proteins in the comparison of SAP and normal samples, and 910 proteins in the comparison of SAP and AP samples. Based on proteomics and acetylation proteomics analyses, we found that 984 proteins were jointly detected in the comparison of AP and normal samples, 990 proteins in SAP and normal samples, and 728 proteins in SAP and AP samples. Thus, our study offers a valuable resource to understand the proteomic and protein modification atlas in AP.