Background Acute pancreatitis (AP) is a severe inflammatory disorder in which mitochondrial dysfunction and ferroptosis critically drive acinar cell injury. Our previous work suggested a protective role for exogenous milk fat globule-epidermal growth factor 8 (MFG-E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG-E8 mitigates mitochondrial damage and ferroptosis during AP.Methods Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding cassette subfamily E member 1 (ABCE1) in vitro. One mitophagy agonist and two ferroptosis inhibitors were used in both in vitro and in vivo experiments.Results Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe2+ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice.Conclusion Endogenous MFG-E8 protects against AP by binding ABCE1 to sustain mitophagy flux and inhibit ferroptosis. Targeting this axis offers a promising therapeutic strategy for mitigating pancreatic injury.Key points Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe2+ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.

Breast cancer continues to be a leading cause of cancer-related mortality in women globally, where precise diagnosis and clear tumor demarcation are critical for effective treatment. Herein, we developed a strategic platform that combines a novel ultrasensitive magnetic resonance (MR) contrast agent with deep learning to significantly enhance the tumor-to-normal ratio (TNR). We designed ultrasmall iron oxide nanoparticles (USIO NPs) conjugated with trastuzumab (Tmab) for targeted MR imaging of HER2-positive breast cancer. The USIO@Tmab nanoprobe demonstrated excellent HER2 specificity and pH-responsive activation. The relaxivity of the nanoprobe shifted from a low T1-weighted intensity (r1 = 1.43 mM- 1s- 1) under physiological conditions to an enhanced value (r1 = 4.07 mM- 1s- 1) in the acidic tumor microenvironment due to the detachment of Tmab protein. Additionally, we employed the 3D nnU-Net deep learning framework as a post-processing visualization aid to enhance tumor boundary detection via image fusion, rather than to amplify the underlying MRI signal. This approach yielded high segmentation accuracy, with an Intersection-over-Union (IoU) of 0.88 and a Dice coefficient of 0.93. This strategy provided an additional 2.59-fold increase in TNR and enabled the reconstruction of three-dimensional (3D) tumor models, offering clinicians an intuitive visualization of tumor structure for precise diagnosis and surgical guidance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is shaped by metabolic injury and tissue mechanics. This study investigated whether liver stiffening occurs early in MASLD and how extracellular matrix (ECM) mechanics interact with lipid droplet (LD) overload to promote inflammation, fibrogenesis, and lipid dysmetabolism. Clinical data, mouse models, and in vitro experiments are integrated. Liver stiffness shifted modestly with steatosis but increased substantially in the presence of inflammation. In a diet-induced mouse model, liver stiffness increased before overt fibrosis. In cultured hepatocytes, stiff matrices combined with free fatty acid (FFA) induced steatosis synergistically amplified pro-inflammatory and pro-fibrotic signals, accompanied by cytoskeletal remodeling and nuclear deformation. YAP acted as a central mechanosensitive amplifier: stiffness drove YAP nuclear localization, and YAP knockdown blunted cytokine induction and fibrogenic gene expression under stiff + FFA conditions. Stiffness and LD overload jointly promoted lipogenesis and impaired lipophagy via YAP. Piezo1 is upregulated by stiff + FFA; its inhibition reduced Ca2⁺ influx and prevented YAP activation. Collectively, early liver stiffening, together with LD-derived intracellular stress, engages a Piezo1-YAP axis that amplifies inflammation, fibrogenesis, and disordered lipid metabolism, consistent with a proposed feed-forward loop mechanism accelerating MASLD progression.

Pancreatic fibrosis is an important pathogenesis of chronic pancreatitis (CP), and the activation of pancreatic stellate cells (PSCs) caused by chronic inflammation plays a key role in this process. Cold-inducible RNA-binding protein (CIRP) is a stress response protein involved in acute inflammation and tissue fibrosis. However, its role in pancreatic fibrosis has not been elucidated. Serum CIRP levels were measured in 17 CP patients and 34 healthy controls. Two mouse models of CP (intraperitoneal administration of L-arginine or cerulein) were employed for in vivo studies. CIRP gene knockout (Cirp-KO) was utilized to downregulate CIRP in mice. C23, a specific inhibitor of CIRP, was used to antagonize CIRP activity in experimental CP. NLRP3 inhibitors or disulfiram were used to block pancreatic cell pyroptosis in CP mice. Serum CIRP levels were elevated in both CP patients and in a mouse model of CP. This increase in CIRP was positively correlated with the severity of pancreatic fibrosis and pyroptosis in experimental CP. Genetic deletion of CIRP or intraperitoneal administration of C23 mitigated pancreatic fibrosis in CP mice. Mechanistically, the pro-fibrotic effects of CIRP appear to be mediated through the TLR4 receptor and the induction of pyroptosis. Accordingly, specific inhibition of TLR4 or blockade of pyroptosis effectively reduced pancreatic inflammation and fibrosis in CP mice, without altering serum CIRP levels. Collectively, our data indicate that CIRP plays a significant role in experimental CP. Inhibition of CIRP alleviates pyroptosis and ameliorates the inflammatory microenvironment in pancreatic tissue, thereby retarding the progression of pancreatic fibrosis. This study primarily provides preclinical evidence elucidating a novel mechanism, and the translational relevance to human disease requires further validation.

Ferroptosis has emerged as a viable approach to enhance therapeutic efficacy in triple-negative breast cancer (TNBC), making monitoring essential for prognostic evaluation. However, conventional MR imaging cannot characterize ferroptosis-related biomarkers. Herein, we propose a Relaxation Suppressed Exchange Tuning (ReSET) MRI strategy for ferroptosis modulation and monitoring, which relies on T1 relaxation and chemical exchange saturation transfer (CEST). ReSET was achieved by a tumor-microenvironment-responsive nanoprobe (SiO2@FUDR@MnO2, SiFM), consisting of a mesoporous silica core loaded with chemotherapeutic floxuridine and the MnO2 shell with nanozyme activities. This structure promotes robust ROS generation, which induces lipid peroxidation and ultimately facilitates chemodynamic therapy (CDT)-sensitized ferroptosis. Notably, ReSET takes advantage of the tumor-responsive release of Mn2+ from SiFM, which shortens T1 relaxation and suppresses the saturation transfer efficiency between water and exchangeable endogenous protons reducing magnetization transfer ratio asymmetry (MTRasym). The inverse correlation between the T1 intensity and MTRasym provides a sensitive and specific indicator for visualizing glutathione peroxidase 4 (GPX4) expression, thereby enabling cross-modal monitoring of ferroptosis. Meanwhile, we revealed that the ReSET strategy enables sensitive detection of small lesions in liver micrometastasis models. Overall, we establish a ReSET MRI-guided strategy using a manganese-based nanoplatform, which represents a promising ferroptosis-related theranostic approach for TNBC.

Despite advances in targeted therapy for HER2-positive breast cancer, tumor-intrinsic resistance mechanisms including defective antigen presentation and adaptive immune suppression remain a significant challenge, constraining therapeutic efficacy. In this study, we developed a multifunctional nanotherapeutic system based on tumor-selective antibody-drug conjugate (ADC) disitamab vedotin (RC48) that co-delivered PEGylated black phosphorus (BP) and resiquimod (R848, a TLR7/8 agonist), thereby enhancing photothermal tumor ablation while activating antitumor immunity in HER2-positive breast cancer. The formed BP-PEG-RC48-R848 nanocomposites exhibited favorable photothermal stability and effectively induced the maturation of dendritic cells while promoting the secretion of pro-inflammatory M1 cytokines. In vivo fluorescence imaging demonstrated specific accumulation of the nanocomposites within HER2-positive tumors. Under near-infrared laser irradiation, the HER2-targeting nanocomposites effectively ablated primary local tumors and elicited concomitant immune activation, collectively inhibiting tumor progression in vivo. By integrating ADC drugs with photothermal-immunotherapy, the nanocomposites demonstrated enhanced precision and synergistic antitumor efficacy of HER2-positive breast cancer.

RNA N6-methyladenosine (m6A) is a common RNA modification in eukaryotes, and its abnormal regulation is closely related to cancer progression. Aerobic glycolysis is a main way for cancer cells to obtain energy. It was found that beaded filament structural protein 1 (BFSP1) is a m6A related gene in liver cancer. However, the effect of m6A-modified BFSP1 on aerobic glycolysis and how it is regulated in liver cancer progression have not been explored. Here, we found that BFSP1 was upregulated in liver cancer cells and tissues. Overexpression of BFSP1 promoted the viability, invasion, and aerobic glycolysis of liver cancer cells, whereas knockdown of BFSP1 showed the opposite effects. Co-immunoprecipitation, immunofluorescence and GST pull down analyses showed that BFSP1 directly interacted with tropomodalin 4 (TMOD4), and knockdown of TMOD4 reversed BFSP1 overexpression-induced malignant phenotypes and aerobic glycolysis in liver cancer cells. Moreover, methyltransferase-like 3 (METTL3) enhanced BFSP1 stability by augmenting m6A modification of BFSP1 mRNA, which is achieved in a YTHDF1-dependent manner. In vivo experiments in mice confirmed that METTL3 increased BFSP1 stability by promoting m6A modification of BFSP1 mRNA, and knockdown of BFSP1 inhibited tumor growth and metastasis. In summary, METTL3-mediated m6A methylation of BFSP1 mRNA plays an important role in the aerobic glycolysis and progression of liver cancer, providing a potential therapeutic strategy for liver cancer.

Bile reflux, resulting from pancreaticobiliary reflux (PBR), not only alters the chemical of bile but also constitutes a significant risk factor for the occurrence and development of gallbladder cancer. In previous studies, the authors identified a marked elevation of palmitic acid (PA) levels in the bile of patients with PBR. This study seeks to elucidate the mechanisms of promoting the migration of gallbladder cancer cells, with the objective of contributing novel strategies and theoretical foundations for the treatment of gallbladder cancer. We performed a cytotoxicity screening on the NOZ and GBC-SD human gallbladder cancer cell line using varying concentrations of palmitic acid. These following methodologies were employed to investigate the mechanism of PA in NOZ and GBC-SD cells. Intracellular lipid droplet accumulation was assessed using Oil red O staining, while cell migration capability was evaluated through the Transwell migration assay. Reactive oxygen species (ROS) levels were quantified using the superoxide anion fluorescent probe, Dihydroethidium (DHE), in conjunction with a ROS detection kit. The expression levels of relevant genes and proteins were analyzed using Western blot (WB), quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence (IF) techniques. In NOZ and GBC-SD cells, it was observed that palmitic acid facilitates the accumulation of intracellular lipid droplets and diminishes cellular activity while augmenting the cells’ migratory capacity. Furthermore, elevated concentrations of PA have been shown to increase ROS levels in NOZ and GBC-SD cells. This elevation also activates the Nuclear factor-kappa B (NF-κB) and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Element (ARE) signaling pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) to NOZ and GBC-SD cells treated with high concentrations of PA effectively inhibits the enhancement of cell migration and epithelial-mesenchymal transition (EMT) induced by PA. PA promotes EMT in human gallbladder cancer cells by overproducing ROS and activating the NF-κB and NRF2/ARE signaling pathways, thereby facilitating increased migration.

OBJECTIVE:To compare the efficacy and safety of radical extrahepatic cyst excision (REC), which includes the intrapancreatic bile duct (IPBD), and subtotal extrahepatic cyst excision (SEC), which preserves the IPBD, in treating Todani type I congenital bile duct dilation with IPBD involvement (I-IPBD). BACKGROUND:The application of REC and SEC in I-IPBD remains debated. METHODS:The multicenter study recruited I-IPBDs who underwent REC or SEC from 5 centers between 2006 and 2024. The primary endpoint was occurrence of long-term complications, including recurrent cholangitis, pancreatitis, and IPBD stones. The secondary outcomes included readmission, reoperation, life quality assessed by Mayo score, carcinogenesis, and perioperative complications categorized as overall, severe, pancreas-related, and severe pancreas-related. RESULTS:Three hundred fifty-five I-IPBDs were included and divided into the REC group (175 cases) and SEC (180 cases) from 722 type I congenital bile duct dilations. The REC group demonstrated better long-term complication-free survival compared with SEC group (log-rank P < 0.001; hazard ratio = 0.08, 95% CI: 0.04-0.15, P < 0.001). The REC group had lower rates of readmission, reoperation, and carcinogenesis, and achieved a superior Mayo score ( P < 0.05). No significant differences were observed between the REC and SEC groups in overall perioperative complications, severe perioperative complications, and severe pancreas-related perioperative complications ( P > 0.05). Furthermore, subgroup analysis by age demonstrated similar trends in primary and secondary outcomes compared with the overall analysis. CONCLUSIONS:REC was an effective and safe surgical approach for I-IPBD compared with SEC, thus it should be recommended routinely for these patients.

The N6-methyladenosine (m6A) methylase WTAP has been identified as a proto-oncogene in multiple cancers, including hepatocellular carcinoma (HCC). Interestingly, although WTAP expression does not differ between normal liver and HCC tissues or across different stages of HCC, patients with higher WTAP expression exhibit significantly shorter median survival times (MSTs). Here, we found that WTAP was upregulated in tumor-infiltrating CD8+ T cells, which were more enriched in HCC patients compared to the controls. HCC patients also displayed higher PD1 levels and a greater proportion of exhausted CD8+ T cells (TCF+ PD1+). Moreover, WTAP promoted PD1 expression and suppressed the proliferation and immune activity of CD8+ T cells. In the co-culture system, WTAP-overexpressing CD8+ T cells enhanced the malignancy of HCC cells. Notably, WTAP silencing further augmented the boosting effect of PD1 silencing on CD8+ T cell immune activity and strengthened its inhibitory effect on HCC cell growth. As an m6A "writer", WTAP increased the m6A level of PD1 mRNA, thereby promoting YTHDF1-mediated translation of PD1. Finally, in the HuNSG xenograft tumor model, WTAP knockdown not only alleviated CD8+ T cell exhaustion and inhibited tumor progression but also synergistically enhanced the antitumor efficacy of anti-PD1 therapy. In conclusion, WTAP promoted CD8+ T cell exhaustion and HCC progression by facilitating the m6A modification and translation of PD1 mRNA.

To compare the efficacy and safety of radical extrahepatic cyst excision (REC), which includes the intrapancreatic bile duct (IPBD), and subtotal extrahepatic cyst excision (SEC), which preserves the IPBD, in treating Todani type I congenital bile duct dilation with IPBD involvement (I-IPBD). The application of REC and SEC in I-IPBD remains debated. The multicenter study recruited I-IPBDs who underwent REC or SEC from 5 centers between 2006 and 2024. The primary endpoint was occurrence of long-term complications, including recurrent cholangitis, pancreatitis, and IPBD stones. The secondary outcomes included readmission, reoperation, life quality assessed by Mayo score, carcinogenesis, and perioperative complications categorized as overall, severe, pancreas-related, and severe pancreas-related. Three hundred fifty-five I-IPBDs were included and divided into the REC group (175 cases) and SEC (180 cases) from 722 type I congenital bile duct dilations. The REC group demonstrated better long-term complication-free survival compared with SEC group (log-rank P < 0.001; hazard ratio = 0.08, 95% CI: 0.04–0.15, P < 0.001). The REC group had lower rates of readmission, reoperation, and carcinogenesis, and achieved a superior Mayo score (P < 0.05). No significant differences were observed between the REC and SEC groups in overall perioperative complications, severe perioperative complications, and severe pancreas-related perioperative complications (P > 0.05). Furthermore, subgroup analysis by age demonstrated similar trends in primary and secondary outcomes compared with the overall analysis. REC was an effective and safe surgical approach for I-IPBD compared with SEC, thus it should be recommended routinely for these patients.

Ferroptosis-based therapy has garnered considerable attention for its ability to kill drug-resistant cancer cells. Consequently, it holds great significance to assess the therapeutic outcomes by monitoring ferroptosis-related biomarkers, which enables the provision of real-time pathological insights into disease progression. Nevertheless, conventional imaging technology suffers from limitations including reduced sensitivity and difficulty in achieving real-time precise monitoring. Here, we report a tumor acidic-microenvironment-responsive nanoplatform with "Reverse Magnetic Resonance Tuning (ReMRT)" property and effective combined chemodynamic therapy (CDT) through the loading of chemotherapeutic drugs. This reverse MR mapping change is correlated with iron ion, reactive oxygen species (ROS) generation and drug release, etc., contributing to the precise monitoring of chemo-CDT effectiveness. Furthermore, the ReMRT nanoplatform presents as a highly efficacious combined chemo-CDT agent, and when this nanoplatform is used in conjunction with the "Area Reconstruction" method, it can afford a significant sensitivity (95.1-fold) in multiscale visualization of therapeutic, compared with the conventional MR R1/R2 values. The high-sensitive biological quantitative imaging provides a novel strategy for MR-guided multiscale dynamic tumor-related ferroptosis therapy.

The accurate non-invasive monitoring of pyroptosis-based immunotherapy is hindered by the lack of sensitive imaging strategies. Here, a self-amplifying chemical exchange saturation transfer (CEST) imaging-guided pyroptosis therapy (pyropCEST) strategy for activating and highly sensitive visualizing pyroptosis-induced immune response is reported. The biocompatible nanoplatform, composed of human serum albumin loaded with gemcitabine, can induce pyroptosis in the tumor microenvironment, promoting dendritic cell maturation and T cell activation. Meanwhile, nanoprobe dissociation enhances chemical exchange between the NH2 groups within gemcitabine/albumin and bulk water, yielding self-amplified CEST signals and boosting imaging sensitivity to 435% compared to normal physiological conditions. In the subcutaneous tumor mouse model, the long-term accumulation of nanoprobes in the tumor leads to a 2.5-fold increase in CEST signal over free gemcitabine. Changes in CEST signal serve as an indicator for evaluating CD8(+) T cell infiltration and tumor growth, exhibiting an excellent "theranostic correlation." Moreover, integration with multiparametric MRI enables comprehensive tracking of therapeutic outcomes, including suppression of distant metastases. Collectively, this pyropCEST strategy introduces a clinically translatable imaging paradigm for non-invasive, dynamic visualization of pyroptosis and immune microenvironment remodeling.

Acidity-activatable magnetic resonance imaging (MRI) nanoprobes offer great potential for in vivo cancer imaging by targeting the acidic tumor microenvironment (TME). However, their effectiveness is limited by the delayed response at tumor sites and uncontrollable background noise, compromising imaging accuracy and reliability. Herein, an acidic TME-responsive nanoprobe, SPIO@ZIF-8@Gd (SZG), with dually activatable T1 and T2 MR signals is shown for acidity-selective contrast enhancement in a rapid response manner. It shows decreased T1 and T2 contrast intensity in normal physiological conditions. Once targeting acidic TME, the zeolitic imidazolate framework-8 (ZIF-8) layer undergoes instantaneous decomposition, releasing Gd3+ (T1-weighted), and exposing the inner SPIO (T2-weighted) core, thereby sequentially recovering the signals. Compared to previously reported T1-T2 nanoprobes, SZG demonstrates noticeable “dual activation” after just 30 min and reaches its peak 4 h after acid incubation. Additionally, it shows an excellent “acidity correlation” between relaxation times and pH values. When the SZG nanoprobe is used combined with “dual-contrast enhanced subtraction (DESI)”, the contrast difference between diseased and normal tissue can be increased by 10 times, which is significantly higher than traditional single-mode T1/T2 contrast agents. Collectively, these findings demonstrate a rapid imaging strategy of dual-activation MR imaging of the acidic TME and simultaneous background suppression, thus paving the way for precise tumor malignancy differentiation, early tumor detection, and accurate tumor grading.

Hypoxia is a hallmark of solid tumors. Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, and CAF-derived exosomes are involved in cancer genesis and progression. Here, this work investigated the role and mechanism of exosomal circHIF1A derived from hypoxia-induced CAFs in hepatocellular carcinoma (HCC) tumorigenesis. CAFs isolated from fresh HCC tissues were incubated in normoxia or hypoxia condition (N/CAFs or H/CAFs), and then the exosomes from N/CAFs or H/CAFs were isolated for functional analysis. Cell proliferation, migration and invasion were analyzed by cell counting kit-8, colony formation, and transwell assays. Immune evasion was evaluated by measuring the cytotoxicity and viability of CD8+T cells. qRT-PCR and western blotting analyses were used for the level measurement of genes and proteins. The binding between Hu antigen R (HuR) and circHIF1A or Programmed death ligand 1 (PD-L1) was analyzed by RNA immunoprecipitation assay. Functionally, we found that CAFs, especially CAFs under hypoxic stress (H/CAFs), promoted the proliferation, migration, invasion and EMT progression in HCC cells, as well as induced immune escape by suppressing CD8+T cell cytotoxicity and activity in an exosome-dependent manner. H/CAFs-derived exosomes showed highly expressed circHIF1A, and could secrete circHIF1A into HCC cells via exosomes. The oncogenic effects of H/CAFs-secreted exosomes were abolished by circHIF1A knockdown. Mechanistically, circHIF1A interacted with HuR to stabilize PD-L1 expression in HCC cells. Meanwhile, circHIF1A silencing suppressed HCC cell proliferation, mobility and immune escape by regulating PD-L1 expression. In all, exosomal circHIF1A derived from hypoxic-induced CAFs promoted the proliferation, migration, invasion, EMT progression and immune escape in HCC cells by up-regulating PD-L1 expression in a HuR-dependent manner.

Background Researches have shown that bile acids (BAs) is related to many tumors. However, the prognosis of intrahepatic cholangiocarcinoma (ICC) is poor. Therefore, this study explore biomarkers related to BAs metabolism and its regulatory mechanism in ICC. Methods TCGA-CHOL was downloaded from The Cancer Genome Atlas Program database. GSE107943, GSE26566, GSE32879 and GSE45001 were obtained from the Gene Expression Omnibus database. 57 bile acids metabolism-related genes (BARGs) were obtained. The candidate genes were obtained by difference analysis, KM survival analysis and machine learning. Next, independent prognostic factors were determined by univariate and multivariate analysis. Meanwhile, functional enrichment, immune infiltration and drug sensitivity analysis of biomarkers were performed, and the mechanism of biomarkers in ICC was explored. Finally, the expression levels of biomarkers were verified in different datasets. Results 40 differentially expressed BARGs (DE-BARGs) were obtained, among 18 genes were significantly associated with prognosis. CYP8B1 , SCP2 , SLC51A and SLCO1A2 were obtained as biomarkers, and SLCO1A2 was used as independent prognostic factor. Also, four biomarkers were correlated with Monocyte and Memory B cells, and seven immune cells were significantly associated with ICC prognosis. Besides, a ceRNA network was established, among SCP2 and SLCO1A2 were regulated through hsa-miR-543 and AC005261.1. Meanwhile, 61 drugs existed diversity between high and low expression groups of biomarkers. Finally, SCP2 and CYP8B1 were significantly expressed in the four data sets. Conclusion CYP8B1 , SCP2 , SLC51A and SLCO1A2 were identified as biomarkers related to BAs metabolism in ICC, which guided the clinical treatment of ICC patients.

BACKGROUND:Portal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of gastrointestinal bleeding. Mucosal apoptosis is an essential pathological feature of PHG. However, whether HIF-1α and p53 are involved in mucosal apoptosis and whether HIF-1α induces PHG by mediating p53 remains unclear.METHODS:Gastric mucosal injury and apoptosis were examined in PHG patients and animal models. The mechanisms of HIF-1α- and p53-mediated apoptosis were analyzed. The GES-1 cell line was used to elucidate the underlying mechanisms using siRNA knockdown of HIF-1α and p53 in a hypoxic environment in vitro.RESULTS:Epithelial apoptosis, HIF-1α, and p53 were markedly induced in the gastric mucosa of PHG. Apoptosis was attenuated in mice with HIF-1α- and p53-specific inhibitors. Apoptotic signaling factors were markedly induced in the gastric mucosa of PHG. Inhibition of p53 demonstrably attenuated the mucosal apoptosis; however, it did not affect HIF-1α expression. Conversely, targeted deletion of HIF-1α significantly inhibited p53 expression and attenuated the injury and p53-mediated apoptosis. Bax and Bcl-2 expression can be upregulated and downregulated by p53, respectively, to increasecleaved caspase-3 expression, which can be regulated by HIF-1α.CONCLUSIONS:These results indicate that HIF-1α regulates the p53-induced mucosal epithelial apoptotic signaling pathway and that HIF-1α and p53 are potential therapeutic targets for PHG.

Gold nanoparticle (AuNPs) influence the biomedical sciences owing to different potential characteristics and potential features. To date, the bioinspired fabrication of AuNPs is further recognized due to their safety and efficacy. In this study, we synthesized AuNPs using leaf extract of Citrus medica (C. medica) and well-characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and UV-visible analyses. Afterward the selective anticancer effects of biosynthesized AuNPs against HepG2 cells were evaluated by different techniques including MTT, oxidative markers, qPCR, and western blot assays. The results showed that the polyphenols of the C. medica leaf extract was responsible for the bioinspired reduction and stability of the AuNPs with a powder size in the range of 20-50 nm. Additionally, it was seen that biosynthesized AuNPs show selective inhibition on the proliferation of HepG2 (human liver cancer cell line) relative to THLE3 (normal adult liver epithelial cells) via generation of ROS and MDA, reduction of GSH level and SOD activity, and over expression of Bax/Bcl-2 and Caspase-3 mRNA. It was also shown that biosynthesized AuNPs regulate the Wnt signaling pathway through upregulation of phosphorylated GSK-3 beta known as the inactivated form of GSK-3 beta and downregulation of beta-catenin and Cyclin-D1 at protein level. This study may hold great promise for development of NP-based anticancer agents, although it needs further investigations in vivo. (C) 2023 Published by Elsevier B.V. on behalf of King Saud University.

Background: Circulating tumor cells (CTCs) can adsorb and activate platelets to form a microthrombus protective barrier around them, so that therapeutic drugs and immune cells cannot effectively kill CTCs. The platelet membrane (PM) bionic carrying drug system has the powerful ability of immune escape, and can circulate in the blood for a long time.Materials and methods: we developed platelet membrane coated nanoparticles (PM HMSNs) to improve the precise delivery of drugs to tumor sites and to achieve more effective immunotherapy combined with chemotherapy strategy.Results: Successfully prepared aPD-L1-PM-SO@HMSNs particles, whose diameter is 95-130 nm and presenting the same surface protein as PM. Laser confocal microscopy and flow cytometry experimental results showed that the fluorescence intensity of aPD-L1-PM-SO@HMSNs was greater than SO@HMSNs that are not coated by PM. Biodistribution studies in H22 tumor-bearing mice showed that due to the combined action of the active targeting effect and the EPR effect, the high accumulation of aPD-L1-PMSO@HMSNs in the local tumor was more effective in inhibiting tumor growth than other groups of therapeutic agents.Conclusion: Platelet membrane biomimetic nanoparticles have a good targeted therapeutic effect, which can effectively avoid immune clearance and have little side effects. It provides a new direction and theoretical basis for further research on targeted therapy of CTCs in liver cancer.& COPY; 2023 Elsevier Inc. All rights reserved.

The development of microenvironment-responsive nanoprobes has shown great promise for use in magnetic resonance imaging (MRI), with the advantage of significantly improved specificity and good biocompatibility. However, the clinical application of responsive probes is hampered by a lack of biological sensitivity for early molecular diagnostics and visualizing microenvionment of metabolism reprogramming in tumor progression. Here, we report on a dual-ratiometric magnetic resonance tunable (DMRT) nanoprobe designed by crosslinking different ratios of transferrin chelating gadolinium and superparamagnetic nanoparticles, complexed to a pH responsive biocompatible polymer. This dually activatable nanoprobe enables pH-dependent tumor microenvironment visualization, providing exceptional quantitative pathophysiological information in vitro and in vivo. When used in combination with dual-contrast enhancement triple subtraction imaging technique (DETSI), this smart nanoprobe guarantees the diagnosis of early-stage diseases. We envisage that this novel integrated nanoplatform will provide a new paradigm for the clinical translation of robust DMRT nanoprobes for early disease detection and staging, as well as microenvironment visualization and disease progression monitoring.