Biomedical subjects

Lili Lu

Publications and source records attributed to Lili Lu.

6 recordsLinked to original sources

PubMed2026

Large-Scale Plasma Proteomics Enhances Prediction of Liver-Related Events Among Individuals With Prediabetes and Type 2 Diabetes: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: To develop a protein risk score (ProRS) for predicting liver-related events (LREs) in patients with diabetes and compare its predictive performance with the Fibrosis-4 Index (FIB-4) and an established polygenic risk score. RESEARCH DESIGN AND METHODS: This prospective cohort study included 13 516 individuals with prediabetes and type 2 diabetes (T2D) from the UK Biobank. Cox proportional hazards models and LASSO regression were applied to identify proteins associated with incident LREs and construct the ProRS. Predictive performance was assessed using Harrell's C-index, time-dependent area under the receiver operating characteristic curve, net reclassification improvement and integrated discrimination improvement. RESULTS: Over a median follow-up of 13.5 years, 171 (1.3%) incident LREs occurred. We identified 877 proteins associated with LRE risk, primarily enriched in inflammatory signalling, extracellular matrix remodelling and complement/coagulation cascades. In the training set, we developed a 24-protein ProRS (C-index, 0.842; 95% CI 0.797-0.884) that stratified individuals into low-, medium- and high-risk groups, with 10-year cumulative incidences of LREs of 0.2%, 1.2% and 14.2%, respectively. Compared with the low-risk group, the hazard ratio for LREs was 57.1 (95% CI 31.9-102) in the high-risk group. In the internal validation set, the ProRS model (C-index, 0.876; 95% CI 0.827-0.920) accurately predicted both short- and long-term LREs and outperformed FIB-4 index (C-index, 0.733; 95% CI 0.657-0.807) and polygenic risk score (C-index, 0.636; 95% CI 0.564-0.706). CONCLUSIONS: The protein risk score demonstrated superior performance compared with the FIB-4 index and the polygenic risk score in predicting incident LREs among individuals with prediabetes and T2D. The score allows stratification of individuals according to liver-related risk, though external validation in multi-ethnic cohorts is warranted.

Humans↗

PubMed2025

Engineering TME-activated CD47-specific CAR macrophage via Arg1 promoter for safe and effective solid tumor immunotherapy.

BACKGROUND: Chimeric antigen receptor macrophage (CAR-Mφ) therapy has promising therapeutic potential in solid tumors, yet challenges remain in target compatibility and systemic toxicity. METHODS: In this study, we screened the CD47-scFv sequence of CAR-Mφ as the extracellular structure. We then constructed a classical CD47 CAR-Mφ incorporated the costimulatory domain of the α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component. Subsequently, we developed a tumor microenvironment (TME)-responsive CAR macrophage platform by the arginase 1 (Arg1) promoter to target CD47, a highly expressed but clinically challenging immune checkpoint in solid tumors. RESULTS: We found that anti-CD47-scFv-mediated macrophages can effectively kill tumor cells both in vivo and in vitro. Furthermore, by integrating an α1β1 integrin-mediated FcγRI signaling domain, CD47 CAR-Mφ exhibited superior antitumor activity in hCD47+4T1 and SGC-7901 cells in vitro, which demonstrated that the CD47 CAR-Mφ was effective against solid tumors. Subsequently, Arg1-mediated activated pArg1 CD47 CAR-Mφ exhibited strong cytotoxicity against target cancer cells. We further demonstrated TME-controllable CAR gene expression in situ and induced a significant regression of established tumors in vivo. Besides, TME-dependent activation of CD47 CAR Mφ reduced the cytotoxic killing effect on erythrocytes. CONCLUSIONS: Our findings confirmed that the TME-specific activation mechanism of pArg1 CD47 CAR-Mφ based on intrinsic Arg1 promoter reprogramming endowed CAR-Mφ to effectively mitigate erythrocyte toxicity while enabling safe multidose administration regimens. This Trojan horse-like CAR-Mφ system achieves tumor-specific activation while minimizing systemic toxicity, offering a novel strategy to expand CAR-Mφ applications for solid tumors.

Animals↗

PubMed2006

Antioxidants reduce cone cell death in a model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit.

Animals↗

PubMed2006

Effects of different types of oxidative stress in RPE cells.

Oxidative damage to retinal pigmented epithelial (RPE) cells and photoreceptors has been implicated in the pathogenesis of age-related macular degeneration (AMD). In order to develop new treatments, it is necessary to characterize the antioxidant defense system in RPE cells to better define their vulnerabilities and how they can be remedied. In this study, we sought to investigate the effects of three different types of oxidative stress on cultured RPE cells. Carbonyl content in RPE cells increased with increasing concentrations of oxidants or increasing duration of exposure with high reproducibility, validating ELISA for carbonyl content as a valuable quantitative measure of oxidative damage. Compared to other cell types, RPE cells were able to survive exposure to H2O2 quite well and exposure to paraquat extremely well. Comparison of the total amount of oxidative damage at the IC50 for each type of stress showed a rank order of hyperoxia > paraquat > H2O2, and since these stressors primarily target different cellular compartments, it suggests that the endogenous defense system against oxidative damage in RPE cells protects well against damage to mitochondria and endoplasmic reticulum, and is less able to handle oxidative damage at the cell surface. Supplementation of media with ascorbic acid provided significant protection from H2O2-induced oxidative damage, but not that induced by paraquat or hyperoxia. Supplementation with docosahexaenoic acid or alpha-tocopherol significantly reduced oxidative damage from H2O2 or hyperoxia, but not that induced by paraquat. We conclude that exposure to different types of oxidative stress results in different patterns of accrual of oxidative damage to proteins in RPE cells, different patterns of loss of viability, and is differentially countered by antioxidants. This study suggests that multiple types of oxidant stress should be used to probe the vulnerabilities of the retina and RPE in vivo, and that ELISA for carbonyl content provides a valuable tool for quantitative assessment of oxidative damage for such studies.

Adult↗

PubMed2005

Retinal degeneration from oxidative damage.

Paraquat, a herbicide that generates reactive oxygen species, has been used to probe the oxidative defense systems of lung. In this study, we investigated the effects of paraquat in the retina. There was no significant decline in electroretinogram (ERG) a- or b-wave amplitudes after intravitreous injection of 1 mul of 0.5 mM paraquat in C57BL/6 mice, but loss of ERG function occurred after injection of 0.75 or 1 mM paraquat. Histology in paraquat-injected eyes showed condensation of chromatin and thinning of the inner and outer nuclear layers indicating cell death, and terminal deoxynucleotidyl transferase-mediated duTP-biotinide end labeling demonstrated that one mechanism of cell death was apoptosis. Fluorescence in the retina and retinal pigmented epithelium after intraocular injection of paraquat followed by perfusion with hydroethidine indicated high levels of superoxide radicals, and oxidative damage was demonstrated by staining for acrolein and enzyme-linked immunosorbent assay for carbonyl adducts. Paraquat-induced damage to the outer nuclear layer was greater in BALB/c mice than in C57BL/6 mice, suggesting strain differences in the oxidative defense system of photoreceptors and/or other modifier genes. Intravitreous injection of paraquat provides a new model of oxidative damage-induced retinal degeneration that is likely to be useful for testing new antioxidant treatments.

Animals↗

PubMed2002

Immobilized receptor- and transporter-based liquid chromatographic phases for on-line pharmacological and biochemical studies: a mini-review.

This review addresses the synthesis and characterization of two different types of receptor-based liquid chromatographic supports, one based upon a trans-membrane ligand gated ion channel receptor (the nicotinic acetylcholine receptor) and the other a soluble nuclear receptor (the estrogen receptor). In addition, studies with the P-glycoprotein transporter are also reported. The nicotinic receptor was immobilized via hydrophobic insertion into the interstitial spaces of an immobilized artificial membrane (IAM) stationary phase. the estrogen receptor was tethered to a hydrophilic stationary phase and the membranes containing the Pgp transporter were coated on the surface of the IAM stationary phase. The stationary phases were characterized using known ligands and substrates for the respective non-immobilized proteins. The results from zonal and frontal chromatographic experiments demonstrated that the stationary phases could be used to determine binding affinities (expressed as dissociation constants, Kd,'s) and to resolve mixtures of ligands according to their relative affinities. In addition. competitive ligand binding studies on the P-glycoprotein-based stationary phase have established that this phase can be used to identify and characterize competitive displacement and allosteric interactions. These studies demonstrate that immobilized-receptor phases can be used for on-line pharmacological studies and as rapid screens for the isolation and identification of lead drug candidates from complex biological or chemical mixtures.

ATP Binding Cassette Transporter, Subfamily B, Mem↗