Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Lactobacillus-derived indole derivatives ameliorate intestinal barrier damage in rat pups with complementary food administration.

The consumption of complementary foods can bring about diarrhea and intestinal barrier dysfunction in infants. In this study, three different Lactobacillus strains combined with L-tryptophan (Trp) were administered to rat pups with complementary foods. Complementary food feeding caused inflammatory cell infiltration, crypt structure irregularity and goblet cell reduction in the colon tissues of the rat pups. However, the oral administration of Trp combined with Lactiplantibacillus plantarum DPUL-S164 or Limosilactobacillus reuteri DPUL-M94 significantly restored the pathological changes in the colon tissues and inhibited the expression of pro-inflammatory cytokines in the colon and ileum of the rat pups. M94 or S164 combined with Trp intervention could promote the expression of cell differentiation genes and tight junction proteins, and restore the intestinal barrier damage caused by complementary foods in rat pups by activating the aryl hydrocarbon receptors (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In addition, the indole-3-lactic acid (ILA), indole-3-propionic acid (IPA), or indole-3-carbaldehyde (I3C) level in the cecal contents of the rat pups increased after intervention of Trp combined with S164 or M94, which may account for the amelioration of intestinal barrier damage in rat pups administered with complementary foods. Furthermore, S164 or M94 combined with Trp intervention up-regulated the relative abundance of f_Lactobacillaceae, f_Akkermansiaceae, g_Lactobacillus, and g_Akkermansia in the intestinal tract of the rat pups. In conclusion, S164 or M94 combined with Trp intervention can ameliorate complementary food-induced intestinal barrier damage and gut flora disorder in rat pups by producing ILA, IPA, or I3C, which are AhR ligands.

MXene-Polydopamine-antiCEACAM1 Antibody Complex as a Strategy for Targeted Ablation of Melanoma.

Photothermal therapy (PTT) is a method for eradicating tumor tissues through the use of photothermal materials and photosensitizing agents that absorb light energy from laser sources and convert it into heat, which selectively targets and destroys cancer cells while sparing healthy tissue. MXenes have been intensively investigated as photosensitizing agents for PTT. However, achieving the selectivity of MXenes to the tumor cells remains a challenge. Specific antibodies (Ab) against tumor antigens can achieve homing of the photosensitizing agents toward tumor cells, but their immobilization on MXene received little attention. Here, we offer a strategy for the selective ablation of melanoma cells using MXene-polydopamine-antiCEACAM1 Ab complexes. We coated Ti3C2Tx MXene with polydopamine (PDA), a natural compound that attaches Ab to the MXene surface, followed by conjugation with an anti-CEACAM1 Ab. Our experiments confirm the biocompatibility of the Ti3C2Tx-PDA and Ti3C2Tx-PDA-antiCEACAM1 Ab complexes across various cell types. We also established a protocol for the selective ablation of CEACAM1-positive melanoma cells using near-infrared irradiation. The obtained complexes exhibit high selectivity and efficiency in targeting and eliminating CEACAM1-positive melanoma cells while sparing CEACAM1-negative cells. These results demonstrate the potential of MXene-PDA-Ab complexes for cancer therapy. They underline the critical role of targeted therapies in oncology, offering a promising avenue for the precise and safe treatment of melanoma and possibly other cancers characterized by specific biomarkers. Future research will aim to refine these complexes for clinical use, paving the way for new strategies for cancer treatment.

Bifidobacterium animalis subsp. lactis CCFM1274 relieved allergic asthma symptoms by modifying intestinal tryptophan metabolism in mice.

Approximately two-thirds of patients with asthma, a common inflammatory airway disease, are thought to present with allergies. Probiotics and tryptophan metabolites are becoming increasingly important in treating allergic asthma. This study aimed to identify potential probiotic strains and tryptophan metabolites that could alleviate asthma symptoms. Based on in vitro fermentation experiments, we evaluated variations in probiotic capacity to metabolize tryptophan. Of the eight tested strains, Bifidobacterium animalis subsp. lactis CCFM1274 produced relatively high levels of indole-3-carboxaldehyde (I3C). A mouse model of allergic asthma was established by oral administration of ovalbumin (OVA) and was subjected to oral administration of probiotics. The results demonstrated that treatment with CCFM1274 reduced the tendency for body weight loss and mortality in OVA-induced asthmatic mice. Ingestion of CCFM1274 improved the infiltration of perivascular and peribronchial inflammatory cells in the lung sections stained with hematoxylin and eosin (H&E). This outcome was accompanied by a reduction in the serum levels of OVA-specific immunoglobulin E (OVA-sIgE) and in the levels of IL-10 and IL-17 in the bronchoalveolar lavage fluid (BALF). The linear discriminant analysis effect size (LEfSe) of the gut microbiota showed that CCFM1274 increased the relative abundance of Bifidobacterium. In conclusion, CCFM1274 remodeled intestinal tryptophan metabolism in mice and contributed to the improvement of allergic asthma.

Discovery of Indolo[3,2-c]isoquinoline Derivatives as Novel Top1/2 Dual Inhibitors with Orally Efficacious Antitumor Activity and Low Toxicity.

Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.

Theranostic Nanoplatform Based on Polydopamine-Coated Magnetic Mesoporous Silicon for Precise Cancer Triplex Nanotherapy and Multimodal Imaging.

Although targeted therapy has revolutionized oncotherapy, engineering a versatile oncotherapy nanoplatform integrating both diagnostics and therapeutics has always been an intractable challenge to overcome the limitations of monotherapy. Herein, a theranostics platform based on DI/MP-MB has successfully realized the fluorescence detection of disease marker miR-21 and the gene/photothermal/chemo triple synergetic cancer therapy, which can trace the tumor through photothermal and fluorescence dual-mode imaging and overcome the limitations of monotherapy to improve the treatment efficiency of tumors. DI/MP-MB was prepared by magnetic mesoporous silicon nanoparticles (M-MSNs) loaded with doxorubicin (Dox) and new indocyanine green (IR820), and subsequently coating polydopamine as a "gatekeeper", followed by the surface adsorbed with molecular beacons capable of targeting miR-21 for responsive imaging. Under the action of enhanced permeability retention and external magnetic field, DI/MP-MB were targeted and selectively accumulated in the tumor. MiR-21 MB hybridized with miR-21 to form a double strand, which led to the desorption of miR-21 MB from the polydopamine surface and the fluorescence recovery to realize gene silencing and fluorescence imaging for tracking the treatment process. Meanwhile, with the response to the near-infrared irradiation and the tumor's microacid environment, the outer layer polydopamine will decompose, releasing Dox and IR820 to realize chemotherapy and photothermal therapy. Finally, the ability of DI/MP-MB to efficiently suppress tumor growth was comprehensively assessed and validated both in vitro and in vivo. Noteworthily, the excellent anticancer efficiency by the synergistic effect of gene/photothermal/chemo triple therapy of DI/MP-MB makes it an ideal nanoplatform for tumor therapy and imaging.

Bazedoxifene Inhibits Cell Viability, Colony-Forming Activity, and Cell Migration in Human Non-Small Cell Lung Cancer Cells and Improves the Treatment Efficacy of Paclitaxel and Gemcitabine.

BACKGROUND: Bazedoxifene is a third-generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6-induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non-small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. METHODS: A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. RESULTS: MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose-dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. CONCLUSION: This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.

Emission-based sensing of cobalt (II) and vitamin B12 via a bis-indole derivative.

In this study, a bis-indole compound was synthesized, characterized by 1H NMR, Fourier transform infrared, and mass spectroscopic measurements and used as a selective and efficient probe for the spectrofluorimetric analysis of Co (II). The cobalt-induced quenching in the emission maximum at 567 nm was considered as the analytical signal in calibration studies. When encapsulated in a polymethyl methacrylate (PMMA) matrix, the bis-indole compound exhibited a limit of detection (LOD) of 3.60 × 10-11 M for Co (II). Vitamin B12, which contains a cobalt ion in the center of a corrin ring in its structure, was also successfully quantified using the same probe. The bis-indole compound showed a linear response based on quenching for increasing concentrations of vitamin B12, partially mimicking the contracted tetrapyrrole ring found naturally in the center of vitamin B12. The LOD for vitamin B12 was found to be 76 nm. Promising photophysical properties of the proposed probe, including high molar extinction coefficient, considerable quantum yield (0.46 and 0.64 in tetrahydrofuran and PMMA, respectively), high Stoke's shift and satisfactory photostability, make it a good choice for fluorescence-based Co (II) determination. The ML3-type stoichiometry of the complex between the dye and cobalt was elucidated both by Job's method and by high-resolution mass spectrometry (HR-MS).

[Perioperative Targeted Therapy for Operable, Early Stage NSCLC]. / Zielgerichtete Systemtherapie beim operablen Lungenkarzinom.

Non-small cell lung cancer (NSCLC) is characterized by high recurrence rates in the early stages. In a German cohort, recurrence-free survival after 5 years was 62% (stage IA1), 40.7% (stage IIA) and 28% (stage IIIA). In addition to the perioperative use of immune checkpoint inhibitors, targeted tumor therapy is also making inroads as an innovation from the palliative setting into the early stages. Of particular relevance is the use of the EGFR inhibitor osimertinib, which has been shown to improve overall survival in the adjuvant setting. In this practice-oriented review, we briefly describe the current status of adjuvant targeted therapy and the associated testing and provide an outlook on further developments.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

Preparation and properties of silver-carrying nano-titanium dioxide antimicrobial agents and silicone composite.

The characteristics of dopamine self-polymerization were used to cover the nano-titanium dioxide (TiO2) surface and produce nano-titanium dioxide-polydopamine (TiO2-PDA). The reducing nature of dopamine was then used to reduce silver nitrate to silver elemental particles on the modified nano-titanium dioxide: The resulting TiO2-PDA-Ag nanoparticles were used as antimicrobial agents. Finally, the antibacterial agent was mixed with silicone to obtain an antibacterial silicone composite material. The composition and structure of antibacterial agents were analyzed by scanning electron microscopy, transmission electron microscopy, X-ray photoelectron energy spectroscopy, and X-ray diffraction. Microscopy and the antibacterial properties of the silicone antibacterial composites were studied as well. The TiO2-PDA-Ag antimicrobial agent had good dispersion versus nano-TiO2. The three were strongly combined with obvious characteristic peaks. The antibacterial agents were evenly dispersed in silicone, and the silicone composite has excellent antibacterial properties. Bacillus subtilis (B. subtilis) adhesion was reduced from 246 × 104 cfu/cm2 to 2 × 104 cfu/cm2, and colibacillus (E. coli) reduced from 228 × 104 cfu/cm2 leading to bacteria-free adhesion.

Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes.

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.

Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study.

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

Polydopamine-Based Targeted Nanosystem for Chemo/Photothermal Therapy of Retinoblastoma in a Mouse Orthotopic Model.

Background: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Targeting Lactobacillus johnsonii to reverse chronic kidney disease.

Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1-5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.

Bufalin-Loaded Multifunctional Photothermal Nanoparticles Inhibit the Anaerobic Glycolysis by Targeting SRC-3/HIF-1α Pathway for Improved Mild Photothermal Therapy in CRC.

Purpose: Compared with traditional photothermal therapy (PTT, >50°C), mild PTT (≤45°C) is a promising strategy for tumor therapy with fewer adverse effects. Unfortunately, its anti-tumor efficacy is hampered by thermoresistance induced by overexpression of heat shock proteins (HSPs). In our previous study, we found bufalin (BU) is a glycolysis inhibitor that depletes HSPs, which is expected to overcome thermotolerance of tumor cells. In this study, BU-loaded multifunctional nanoparticles (NPs) were developed for enhancing the mild PTT of colorectal cancer (CRC). Methods: Fe3O4 NPs coated with the polydopamine (PDA) shell modified with polyethylene glycol (PEG) and cyclic arginine-glycyl-aspartic peptide (cRGD) for loading BU (Fe3O4@PDA-PEG-cRGD/BU NPs) were developed. The thermal variations in Fe3O4@PDA-PEG-cRGD/BU NPs solution under different conditions were measured. Glycolysis inhibition was evaluated by measuring the glucose uptake, extracellular lactate, and intracellular adenosine triphosphate (ATP) levels. The cellular cytotoxicity of Fe3O4@PDA-PEG-cRGD/BU NPs was analyzed using a cell counting kit-8 assay, Calcein-AM/PI double staining, and flow cytometry in HCT116 cells. The magnetic resonance imaging (MRI) performance and anti-tumor therapeutic efficacy of Fe3O4@PDA-PEG-cRGD/BU NPs were evaluated in HCT116-tumor bearing mice. Results: Fe3O4@PDA-PEG-cRGD/BU NPs had an average diameter of 260.4±3.5 nm, the zeta potential of -23.8±1.6 mV, the drug loading rate of 1.1%, which had good thermal stability, photothermal conversion efficiencies and MRI performance. In addition, the released BU not only killed tumor cells but also interfered with glycolysis by targeting the steroid receptor coactivator 3 (SRC-3)/HIF-1α pathway, preventing intracellular ATP synthesis, and combating HSP-dependent tumor thermoresistance, ultimately strengthening the thermal sensitivity toward mild PTT both in vitro and in vivo. Conclusion: This study provides a highly effective strategy for enhancing the therapeutic effects of mild PTT toward tumors.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

A melanin-like polymer bearing phenylboronic units as a suitable bioplatform for living cell display technology.

Surface display of functional groups with specific reactivity around living cells is an emerging, low cost and highly eco-compatible technology that serves multiple applications, ranging from basic biochemical studies to biomedicine, therapeutics and environmental sciences. Conversely to classical methods exploiting hazardous organic synthesis of precursors or monovalent functionalization via genetics, here we perform functional decoration of individual living microalgae using suitable biocoatings based on polydopamine, a melanin-like synthetic polymer. Here we demonstrate the one-pot synthesis of a functional polydopamine bearing phenylboronic units which can decorate the living cell surfaces via a direct ester formation between boronic units and surface glycoproteins. Furthermore, biosorption of fluorescent sugars on functionalized cell membranes is triggered, demonstrating that these organic coatings act as biocompatible soft shells, still functional and reactive after cell engineering.