MKLN1-AS promotes pancreatic cancer progression as a crucial downstream mediator of HIF-1α through miR-185-5p/TEAD1 pathway.

In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.

Black Rice Anthocyanins as An Effective Antioxidant of Inhibition of Oil Oxidative Based on Molecular Modification.

This present work investigated the influence of black rice anthocyanins as antioxidants on the oxidation stability of oil. Malonic acid, succinic acid and succinic anhydride were grafted on black rice anthocyanins through acylation method to improve their antioxidant activity in oil. The results from fourier transform infrared spectroscopy (FTIR) showed new absorption peaks near 1744 cm -1 and 1514 cm -1 , which implied that malonic acid, succinic acid and succinic anhydride grafted on the -OH of glucoside and rutinoside through esterification reaction and resulted that the polarity of these were reduced. Total content of anthocyanin (TAC) decreased to 166. 3 mg/g, 163.7 mg/g and 150.2 mg/g, respectively after modification with succinic acid, malonic acid and succinic anhydride. Compared with native anthocyanins, the acylation of black rice anthocyanins partially reduced its antioxidant activity. In addition, DPPH clearance of molecular modified anthocyanins decreased to 62.6% (San-An). As revealed in the oil stability through the determination of primary oxidation products (PV) and secondary oxidation products (p-AV), Sa-An, Ma-An and San-An showed stronger antioxidant activity in Schaal oven accelerated oxidation test during 12 days than native black rice anthocyanin in both corn oil and flaxseed oil. Molecular modified black rice anthocyanins are expected to be used as colorants, antioxidants, etc. in oil-rich food.

Photo-Driven Ion Directional Transport across Artificial Ion Channels: Band Engineering of WS2 via Peptide Modification.

Biological photo-responsive ion channels play important roles in the important metabolic processes of living beings. To mimic the unique functions of biological prototypes, the transition metal dichalcogenides, owing to their excellent mechanical, electrical, and optical properties, are already used for artificial intelligent channel constructions. However, there remain challenges to building artificial bio-semiconductor nanochannels with finely tuned band gaps for accurately simulating or regulating ion transport. Here, two well-designed peptides are employed for the WS2 nanosheets functionalization with the sequences of PFPFPFPFC and DFDFDFDFC (PFC and DFC; P: proline, D: aspartate, and F: phenylalanine) through cysteine (Cys, C) linker, and an asymmetric peptide-WS2 membrane (AP-WS2M) could be obtained via self-assembly of peptide-WS2 nanosheets. The AP-WS2M could realize the photo-driven anti-gradient ion transport and vis-light enhanced osmotic energy conversion by well-designed working patterns. The photo-driven ion transport mechanism stems from a built-in photovoltaic motive force with the help of formed type II band alignment between the PFC-WS2 and DFC-WS2. As a result, the ions would be driven across the channels of the membrane for different applications. The proposed system provides an effective solution for building photo-driven biomimetic 2D bio-semiconductor ion channels, which could be extensively applied in the fields of drug delivery, desalination, and energy conversion.

Biomimicking TRPM8: A Conversely Temperature-Dependent Nonionic Retrorse Nanochannel for Ion Flow Control.

Ion channels play a crucial role in the transmembrane transport and signal transmission of substances. In animals, transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential melastatin 8 (TRPM8) serve as temperature-sensing units in sensory nerve endings. TRPV1 allows cells to sense heat, while TRPM8 enables them to detect cold, both serving to protect living organisms from harmful substances and environments. However, almost all studies on artificial nanochannels have mainly focused on TRPV1-like "forward nanochannels" thus far, which are incapable of "backward" responding to heat. So, we constructed an innovational TRPM8-inspired "retrorse nanochannel" through internal modification of poly(acrylamide-co-acrylonitrile) [P(AAm-co-AN)] with an upper critical solution temperature (UCST). Our results demonstrated that the internally modified nanochannels exhibited rapid, stable, and reversible heat-closing capability and converse temperature dependence within the typical temperature range of 25-40 °C. The biomimetic ion channel can effectively function as a facile, precise, and reversible thermal gate for controlling the transport of ions and substances. It also offers a promising microscopic technology for managing thermal effects on the substance, fluid, energy, and even signal delivery.

Exploring new frontiers: cell surface vimentin as an emerging marker for circulating tumor cells and a promising therapeutic target in advanced gastric Cancer.

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise in guiding treatment strategies for advanced gastric cancer (GC). However, their clinical impact has been limited due to challenges in identifying epithelial-mesenchymal transition (EMT)-CTCs using conventional methods. METHODS: To bridge this knowledge gap, we established a detection platform for CTCs based on the distinctive biomarker cell surface vimentin (CSV). A prospective study involving 127 GC patients was conducted, comparing CTCs enumeration using both EpCAM and CSV. This approach enabled the detection of both regular and EMT-CTCs, providing a comprehensive analysis. Spiking assays and WES were employed to verify the reliability of this marker and technique. To explore the potential inducer of CSV+CTCs formation, a combination of Tandem Mass Tag (TMT) quantitative proteomics, m6A RNA immunoprecipitation-qPCR (MeRIP-qPCR), single-base elongation- and ligation-based qPCR amplification method (SELECT) and RNA sequencing (RNA-seq) were utilized to screen and confirm the potential target gene. Both in vitro and in vivo experiments were performed to explore the molecular mechanism of CSV expression regulation and its role in GC metastasis. RESULTS: Our findings revealed the potential of CSV in predicting therapeutic responses and long-term prognosis for advanced GC patients. Additionally, compared to the conventional EpCAM-based CTCs detection method, the CSV-specific positive selection CTCs assay was significantly better for evaluating the therapeutic response and prognosis in advanced GC patients and successfully predicted disease progression 14.25 months earlier than radiology evaluation. Apart from its excellent role as a detection marker, CSV emerges as a promising therapeutic target for attenuating GC metastasis. It was found that fat mass and obesity associated protein (FTO) could act as a potential catalyst for CSV+CTCs formation, and its impact on the insulin-like growth factor-I receptor (IGF-IR) mRNA decay through m6A modification. The activation of IGF-I/IGF-IR signaling enhanced the translocation of vimentin from the cytoplasm to the cell surface through phosphorylation of vimentin at serine 39 (S39). In a GC mouse model, the simultaneous inhibition of CSV and blockade of the IGF-IR pathway yielded promising outcomes. CONCLUSION: In summary, leveraging CSV as a universal CTCs marker represents a significant breakthrough in advancing personalized medicine for patients with advanced GC. This research not only paves the way for tailored therapeutic strategies but also underscores the pivotal role of CSV in enhancing GC management, opening new frontiers for precision medicine.

A marine bacteria-inspired electrochemical regulation for continuous uranium extraction from seawater and salt lake brine.

Oceans and salt lakes contain vast amounts of uranium. Uranium recovery from natural water not only copes with radioactive pollution in water but also can sustain the fuel supply for nuclear power. The adsorption-assisted electrochemical processes offer a promising route for efficient uranium extraction. However, competitive hydrogen evolution greatly reduces the extraction capacity and the stability of electrode materials with electrocatalytic activity. In this study, we got inspiration from the biomineralisation of marine bacteria under high salinity and biomimetically regulated the electrochemical process to avoid the undesired deposition of metal hydroxides. The uranium uptake capacity can be increased by more than 20% without extra energy input. In natural seawater, the designed membrane electrode exhibits an impressive extraction capacity of 48.04 mg-U per g-COF within 21 days (2.29 mg-U per g-COF per day). Furthermore, in salt lake brine with much higher salinity, the membrane can extract as much uranium as 75.72 mg-U per g-COF after 32 days (2.37 mg-U per g-COF per day). This study provides a general basis for the performance optimisation of uranium capture electrodes, which is beneficial for sustainable access to nuclear energy sources from natural water systems.

Rhein against Staphylococcus xylosus by interfering with respiratory metabolism and inducing oxidative stress.

Currently, dairy mastitis caused by Staphylococcus xylosus poses a serious challenge for dairy farming. In this study, we explored the role and mechanism of rhein against S. xylosus with the hope of providing new research ideas to solve mastitis in dairy cows and ensure the source safety of dairy products. Through in vitro antimicrobial studies, we found that the minimum inhibitory concentration (MIC) of rhein was 64 µg/mL, and it significantly interfered with the formation of S. xylosus biofilm at sub-MIC. In experiments on mastitis in mice, rhein alleviated inflammation in mammary tissue, reduced the levels of TNF-α and IL-6, and decreased the number of S. xylosus. To explore the anti-S. xylosus mechanism of rhein, we identified the relevant proteins involved in carbon metabolism (Glycolysis/gluconeogenesis, TCA cycle, Fatty acid degradation) through proteomics. Additionally, proteins associated with the respiratory chain, oxidative stress (proteins of antioxidant and DNA repair), and nitrate respiration were also found to be upregulated. Thus, rhein may act as an antibacterial agent by interfering with the respiratory metabolism of S. xylosus and inducing the production of ROS, high levels of which alter the permeability of bacterial cell membranes and cause damage to them. We measured the concentrations of extracellular ß-galactosidase and nucleic acids. Additionally, SEM observation of S. xylosus morphology showed elevated membrane permeability and damage to the cell membrane. Finally, RT-PCR experiments showed that mRNAs of key proteins of the TCA cycle (odhA, mqo) and nitrate respiration (nreB, nreC, narG) were significantly up-regulated, consistent with proteomic results. In conclusion, rhein has good anti-S. xylosus effects in vitro and in vivo, by interfering with bacterial energy metabolism, inducing ROS production, and causing cell membrane and DNA damage, which may be one of the important mechanisms of its antimicrobial activity.

Archaea-Inspired Switchable Nanochannels for On-Demand Lithium Detection by pH Activation.

With the rapid development of the lithium ion battery industry, emerging lithium (Li) enrichment in nature has attracted ever-growing attention due to the biotoxicity of high Li levels. To date, fast lithium ion (Li+) detection remains urgent but is limited by the selectivity, sensitivity, and stability of conventional technologies based on passive response processes. In nature, archaeal plasma membrane ion exchangers (NCLX_Mj) exhibit Li+-gated multi/monovalent ion transport behavior, activated by different stimuli. Inspired by NCLX_Mj, we design a pH-controlled biomimetic Li+-responsive solid-state nanochannel system for on-demand Li+ detection using 2-(2-hydroxyphenyl)benzoxazole (HPBO) units as Li+ recognition groups. Pristine HPBO is not reactive to Li+, whereas negatively charged HPBO enables specific Li+ coordination under alkaline conditions to decrease the ion exchange capacity of nanochannels. On-demand Li+ detection is achieved by monitoring the decline in currents, thereby ensuring precise and stable Li+ recognition (>0.1 mM) in the toxic range of Li+ concentration (>1.5 mM) for human beings. This work provides a new approach to constructing Li+ detection nanodevices and has potential for applications of Li-related industries and medical services.

Light-responsive and ultrapermeable two-dimensional metal-organic framework membrane for efficient ionic energy harvesting.

Nanofluidic membranes offer exceptional promise for osmotic energy conversion, but the challenge of balancing ionic selectivity and permeability persists. Here, we present a bionic nanofluidic system based on two-dimensional (2D) copper tetra-(4-carboxyphenyl) porphyrin framework (Cu-TCPP). The inherent nanoporous structure and horizontal interlayer channels endow the Cu-TCPP membrane with ultrahigh ion permeability and allow for a power density of 16.64 W m-2, surpassing state of-the-art nanochannel membranes. Moreover, leveraging the photo-thermal property of Cu-TCPP, light-controlled ion active transport is realized even under natural sunlight. By combining solar energy with salinity gradient, the driving force for ion transport is reinforced, leading to further improvements in energy conversion performance. Notably, light could even eliminate the need for salinity gradient, achieving a power density of 0.82 W m-2 in a symmetric solution system. Our work introduces a new perspective on developing advanced membranes for solar/ionic energy conversion and extends the concept of salinity energy to a notion of ionic energy.

Phospholipase A2 enzymes PLA2G2A and PLA2G12B as potential diagnostic and prognostic biomarkers in cholangiocarcinoma.

BACKGROUND: Phospholipase A2 (PLA2) enzymes are pivotal in various biological processes, such as lipid mediator production, membrane remodeling, bioenergetics, and maintaining the body surface barrier. Notably, these enzymes play a significant role in the development of diverse tumors. AIM: To systematically and comprehensively explore the expression of the PLA2 family genes and their potential implications in cholangiocarcinoma (CCA). METHODS: We conducted an analysis of five CCA datasets from The Cancer Genome Atlas and the Gene Expression Omnibus. The study identified differentially expressed genes between tumor tissues and adjacent normal tissues, with a focus on PLA2G2A and PLA2G12B. Gene Set Enrichment Analysis was utilized to pinpoint associated pathways. Moreover, relevant hub genes and microRNAs for PLA2G2A and PLA2G12B were predicted, and their correlation with the prognosis of CCA was evaluated. RESULTS: PLA2G2A and PLA2G12B were discerned as differentially expressed in CCA, manifesting significant variations in expression levels in urine and serum between CCA patients and healthy individuals. Elevated expression of PLA2G2A was correlated with poorer overall survival in CCA patients. Additionally, the study delineated pathways and miRNAs associated with these genes. CONCLUSION: Our findings suggest that PLA2G2A and PLA2G12B may serve as novel potential diagnostic and prognostic markers for CCA. The increased levels of these genes in biological fluids could be employed as non-invasive markers for CCA, and their expression levels are indicative of prognosis, underscoring their potential utility in clinical settings.

Bioinspired carbon nanotube-based nanofluidic ionic transistor with ultrahigh switching capabilities for logic circuits.

The voltage-gated ion channels, also known as ionic transistors, play substantial roles in biological systems and ion-ion selective separation. However, implementing the ultrafast switchable capabilities and polarity switching of ionic transistors remains a challenge. Here, we report a nanofluidic ionic transistor based on carbon nanotubes, which exhibits an on/off ratio of 104 at operational gate voltage as low as 1 V. By controlling the morphology of carbon nanotubes, both unipolar and ambipolar ionic transistors are realized, and their on/off ratio can be further improved by introducing an Al2O3 dielectric layer. Meanwhile, this ionic transistor enables the polarity switching between p-type and n-type by controlled surface properties of carbon nanotubes. The implementation of constructing ionic circuits based on ionic transistors is demonstrated, which enables the creation of NOT, NAND, and NOR logic gates. The ionic transistors are expected to have profound implications for low-energy consumption computing devices and brain-machine interfacing.

Causal effect of gut microbiota of Defluviitaleaceae on the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism".

Introduction: Hypothyroidism has been found to be influenced by gut microbiota. However, it remains unclear which a taxon of gut microbiota plays a key role in this function. Identifying the key bacteria affects hypothyroidism and through what mechanism will be helpful for the prevention of hypothyroidism through specific clinical pathways. Materials and methods: In Study A, 35 families and 130 genera of gut microbiota are used as exposures, with hypothyroidism as the outcome. The causal effect of the gut microbiota on hypothyroidism is estimated through two-sample Mendelian randomization. Combining the results of the two taxonomical levels, key taxa are selected, which in Study B are investigated for their causal association with multiple generally admitted causes of hypothyroidism and their more upstream factors. For validating and revealing the potential mechanism, enrichment analyses of the related genes and interacting transcription factors were performed. Results: In Study A, Defluviitaleaceae (OR: 0.043, 95% CI: 0.005-0.363, P = 0.018)/Defluviitaleaceae_UCG_011 (OR: 0.385, 95% CI: 0.172-0.865, P = 0.021) are significantly causally associated with hypothyroidism at both taxonomical levels. In Study B, Defluviitaleaceae family and Defluviitaleaceae_UCG_011 genus show the causal association with decreased thyroiditis (Family: OR: 0.174, 95% CI: 0.046-0.653, P = 0.029; Genus: OR: 0.139, 95% CI: 0.029-0.664, P = 0.043), decreased subacute thyroiditis (Family: OR: 0.028, 95% CI: 0.004-0.213, P = 0.007; Genus: OR: 0.018, 95% CI: 0.002-0.194, P = 0.013), decreased influenza (Family: OR: 0.818, 95% CI: 0.676-0.989, P = 0.038; Genus: OR: 0.792, 95% CI: 0.644-0.974, P = 0.027), and increased anti-influenza H3N2 IgG levels (Family: OR: 1.934, 95% CI: 1.123-3.332, P = 0.017; Genus: OR: 1.675, 95% CI: 0.953-2.943, P = 0.073). The results of the enrichment analysis are consistent with the findings and the suggested possible mechanisms. Conclusion: Defluviitaleaceae of the gut microbiota displays the probability of causally inhibiting the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism" and acts as the potential probiotics to prevent influenza, subacute thyroiditis, and hypothyroidism.

Age and incidence of occult pancreaticobiliary reflux in patients with benign gallbladder diseases.

BACKGROUND: Occult pancreaticobiliary reflux (OPBR) has a significant correlation with diseases of the gallbladder and biliary system. This study examined the incidence of OPBR by age in patients with benign gallbladder diseases. METHODS: We assessed 475 patients with benign gallbladder diseases who underwent surgery at Shanghai East Hospital from December 2020 to December 2021. Bile samples collected during surgery were tested for amylase. Patients with bile amylase >110 U/L (n = 64) were classified as the OPBR group; the rest (n = 411) as controls. RESULTS: Of the participants, 375 had gallbladder stone (GS), 170 had gallbladder polyp (GP), and 49 had gallbladder adenomyomatosis (GA). The OPBR group was generally older, with OPBR incidence increasing with age, peaking post-45. Rates by age were: 4.9% (<35), 5.2% (35-44), 20.7% (45-54), 22.5% (55-64) and 17.6% (≥65), mainly in GS patients. ROC analysis for predicting OPBR by age yielded an area under the curve of 0.656, optimal cut-off at 45 years. Logistic regression indicated age > 45, GP, male gender, and BMI ≥ 24 kg*m-2 as independent OPBR predictors in GS patients. Based on these variables, a predictive nomogram was constructed, and its effectiveness was validated using the ROC curve, calibration curve and decision curve analysis (DCA). Further stratification revealed that among GS patients ≤ 45, concurrent GA was an OPBR risk; for > 45, it was GP and male gender. CONCLUSIONS: The incidence of OPBR in GS patients is notably influenced by age, with those over 45, especially males without GP, being at heightened risk.

A Novel Serum Exosomal miRNA Signature in the Early Prediction of Persistent Organ Failure in Patients with Acute Pancreatitis.

OBJECTIVE: Current study aims to investigate whether serum exosomal microRNAs (miRNAs) could be potential biomarkers in predicting APs with POF at early phase. BACKGROUND: Novel biomarkers are sorely needed for early prediction of persistent organ failure (POF) in acute pancreatitis (AP) patients. METHODS: In the discovery stage, exosomal miRNAs were profiled in sera from APs with or without POF (5 vs. 5) using microarrays. POF-associated miRNA signatures then were assessed in training cohort (n=227) and further validated in three independent cohorts (n=516), including one nested case-control cohort. RESULTS: A total of 743 APs were recruited in this large-scale biomarker identification study with a nested case-control study. Data from the discovery cohort demonstrated that 90 exosomal miRNAs were significantly dysregulated in APs with POF compared with controls. One miRNA classifier (Cmi) comprising 3 miRNAs (miR-4265, 1208, 3127-5p) was identified in the training cohort, and was further evaluated in two validation cohorts for their predictive value for POF. AUCs for Cmi ranged from 0.88 to 0.90, which was statistically superior to AUCs of APACHE-II and BISAP, and outperformed BUN and creatinine in POF prediction across all cohorts (P<.05). Higher levels of Cmi indicated increased need for ICU admission, prolonged hospitalization, and elevated mortality rate, thus poor prognosis. In the nested case-control study, Cmi could help identify prediagnostic POF in post-ERCP pancreatitis cases within "golden hours" after ERCP with high efficacy. CONCLUSIONS: Serum exosomal Cmi may be an early predictor for POF in AP, even within "golden hours" after AP onset. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02602808).

Ion transport in nanofluidics under external fields.

Nanofluidic channels with tailored ion transport dynamics are usually used as channels for ion transport, to enable high-performance ion regulation behaviors. The rational construction of nanofluidics and the introduction of external fields are of vital significance to the advancement and development of these ion transport properties. Focusing on the recent advances of nanofluidics, in this review, various dimensional nanomaterials and their derived homogeneous/heterogeneous nanofluidics are first briefly introduced. Then we discuss the basic principles and properties of ion transport in nanofluidics. As the major part of this review, we focus on recent progress in ion transport in nanofluidics regulated by external physical fields (electric field, light, heat, pressure, etc.) and chemical fields (pH, concentration gradient, chemical reaction, etc.), and reveal the advantages and ion regulation mechanisms of each type. Moreover, the representative applications of these nanofluidic channels in sensing, ionic devices, energy conversion, and other areas are summarized. Finally, the major challenges that need to be addressed in this research field and the future perspective of nanofluidics development and practical applications are briefly illustrated.

Current Status of Novel Multifunctional Targeted Pt(IV) Compounds and Their Reductive Release Properties.

Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Engineered bacterial outer membrane vesicles: a versatile bacteria-based weapon against gastrointestinal tumors.

Outer membrane vesicles (OMVs) are nanoscale lipid bilayer structures released by gram-negative bacteria. They share membrane composition and properties with their originating cells, making them adept at traversing cellular barriers. These OMVs have demonstrated exceptional membrane stability, immunogenicity, safety, penetration, and tumor-targeting properties, which have been leveraged in developing vaccines and drug delivery systems. Recent research efforts have focused on engineering OMVs to increase production yield, reduce cytotoxicity, and improve the safety and efficacy of treatment. Notably, gastrointestinal (GI) tumors have proven resistant to several traditional oncological treatment strategies, including chemotherapy, radiotherapy, and targeted therapy. Although immune checkpoint inhibitors have demonstrated efficacy in some patients, their usage as monotherapy remains limited by tumor heterogeneity and individual variability. The immunogenic and modifiable nature of OMVs makes them an ideal design platform for the individualized treatment of GI tumors. OMV-based therapy enables combination therapy and optimization of anti-tumor effects. This review comprehensively summarizes recent advances in OMV engineering for GI tumor therapy and discusses the challenges in the clinical translation of emerging OMV-based anti-tumor therapies.

Identification of changes in bile composition in pancreaticobiliary reflux based on liquid chromatography/mass spectrometry metabolomics.

INTRODUCTION: Pancreaticobiliary reflux (PBR) can induce gallstone formation; however, its pathogenic mechanism remains unclear. In this study, we explored the mechanism of PBR by the non-targeted metabolomic analysis of bile in patients with PBR. OBJECTIVE: The aim of this study was to investigate the pathogenic mechanism in PBR by the non-targeted metabolomic analysis of bile collected during surgery. METHODS: Sixty patients who underwent gallstone surgery at our center from December 2020 to May 2021 were enrolled in the study. According to the level of bile amylase, 30 patients with increased bile amylase ( > 110 U/L) were classified into the PBR group, and the remaining 30 patients were classified into the control group (≤ 110 U/L). The metabolomic analysis of bile was performed. RESULTS: The orthogonal projections to latent structure-discriminant analysis of liquid chromatography mass spectrometry showed significant differences in bile components between the PBR and control groups, and 40 metabolites were screened by variable importance for the projection value (VIP > 1). The levels of phosphatidylcholine (PC) and PC (20:3(8Z,11Z,14Z)/14:0) decreased significantly, whereas the levels of lysoPC (16:1(9z)/0:0), lysoPC (15:0), lysoPC (16:0), palmitic acid, arachidonic acid, leucine, methionine, L-tyrosine, and phenylalanine increased. CONCLUSIONS: Significant differences in bile metabolites were observed between the PBR and control groups. Changes in amino acids and lipid metabolites may be related to stone formation and mucosal inflammation.

Design of balanced dual-target inhibitors of EGFR and microtubule.

Motivated by the clinical success of combining tyrosine kinase inhibitors with microtubule-targeted drugs in antitumor treatment, this paper presents a novel combi-targeting design for dual-target inhibitors, featuring arylformylurea-coupled quinazoline backbones. A series of target compounds (10a-10r) were designed, synthesized, and characterized. Biological assessments demonstrated that 10c notably potentiated ten tumor cell lines in vitro, with IC50 values ranging from 1.04 µM to 7.66 µM. Importantly, 10c (IC50 = 10.66 nM) exhibited superior inhibitory activity against EGFR kinases compared to the reference drug Gefitinib (25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, 10c significantly impeded tubulin polymerization, disrupted the intracellular microtubule network in A549 cells, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration. In anticancer evaluation tests using A549 cancer-bearing nude mice models, 10c showed a therapeutic effect similar to Gefitinib, but required only half the dosage (15 mg/kg). These findings indicate that compound 10c is a promising dual-target candidate for anticancer therapy.