IMMUNITY
·
2026
·
IF 30.6
Dong Guo,Ying Meng,Qingqing Yang,Shudi Luo,Xiaoming Jiang,Yanhua Zheng,Lihui Wu,Suyao Li,Hongfei Jiang,Shan Li,Zheng Wang,Min Li,Qingang Wu,Liwei Xiao,Rongxuan Zhu,Xuxiao He,Yanyan Hu,Hong Zhao,Xianglai Ye,Yingying Tong,Jing Fang,Daqian Xu,Jun Xu,Ying Yuan,Zhimin Lu
In cancer cells, pyruvate generated through aerobic glycolysis is preferentially converted into lactate. Here, we examined the impact of aerobic glycolysis on innate immune regulation within the tumor microenvironment. We identified lactate as a potent suppressor of stimulator of interferon genes (STING)-mediated innate immune signaling. Lactate directly bound the cyclic GMP-AMP (cGAMP)-binding domain of STING, thereby inhibiting cGAMP binding, STING activation, and interferon regulatory factor 3 (IRF3)-dependent cytokine expression. Mechanistically, activation of epidermal growth factor receptor (EGFR) promoted phosphorylation of lactate dehydrogenase A (LDHA) by pyruvate kinase M2 (PKM2) at serine 161 (S161). This increased LDHA activity and lactate production, which suppressed immune cell infiltration and promoted tumor growth. Pharmacological PKM2 inhibition relieved lactate-mediated STING suppression, reduced tumor immune evasion, and synergized with anti-PD-1 therapy. In human glioblastoma, elevated LDHA S161 phosphorylation correlated with reduced STING activation, diminished cytotoxic immune cell infiltration, and poor survival. Thus, oncogenic signaling directs PKM2-generated pyruvate toward LDHA-mediated lactate production, which directly inhibits STING to silence innate immune activation.
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BIOMATERIALS
·
2026
·
IF 13.6
Jin Li,Mengyi Yang,Rui Xing,Jingmei Pan,Xing Guo,Shaobing Zhou
Ischemic stroke therapy remains challenging due to a detrimental post-reperfusion inflammatory cascade that exacerbates neuronal damage, a process critically mediated by neutrophils and microglia. Neutrophils infiltrate the brain to release pro-inflammatory factors and neutrophil extracellular traps (NETs), while microglia become activated and amplify neuroinflammation. However, both cell types possess phenotypic plasticity that allows for immunomodulation toward repair. To address this, we developed a biomimetic nanoparticle strategy designed to reprogram these immune cells. Specifically, we encapsulated rosiglitazone into mPEG-PLA nanoparticles and further coated them with platelet membranes, obtaining a targeted nanoplatform termed pmPELA@R. In a mouse model of middle cerebral artery occlusion (MCAO), the platelet membrane coating markedly enhanced neutrophil targeting and improved brain accumulation of pmPELA@R. The released rosiglitazone activated PPAR-γ to polarize neutrophils toward the N2 phenotype and suppressed NETosis. Concurrently, the lactate generated from PLA degradation promoted microglial M2 polarization via enhanced histone lactylation. This dual modulation synergistically shifted the inflammatory microenvironment toward a reparative state, leading to enhanced neural tissue recovery. Our findings present a novel nanotherapeutic approach for precise immunomodulation in ischemic stroke.
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BMEMat
·
2026
·
IF 17.2
Siyu Pan,Xuanyi Lu,Wenjie Yang,Yunhui Peng,Lingfu Deng,Shuai Zha,Xueyang Fang,Guochen Bao,Lijun Jiang
Intratumoral L-lactate represents a valuable biomarker for both prognosis and therapy response, underscoring the importance of its accurate detection. However, traditional L-lactate assays rely on indirect hydrogen peroxide readouts and often compromise the accuracy and specificity. Herein, we report an aptamer-based nanoprobe (UCNP-Apt-Act) that allows direct L-lactate detection. Aptamers offer high specificity for L-lactate but suffer from poor cellular uptake and premature activation by extracellular L-lactate. To overcome this, we introduced lanthanide-doped upconversion nanoparticles (UCNPs) to enable spatially controlled unlocking by near-infrared (NIR) light for intratumoral L-lactate detection. The nanoprobe remains “locked” during delivery via an engineered actuator, preventing premature response to extracellular L-lactate. Upon 980 nm excitation, UCNPs convert NIR to UV emission, photocleaving the actuator linker and unlocking the aptamer. Notably, the UCNP carriers enhanced cellular uptake by 41 times through overcoming membrane barriers. The unlocked nanoprobe shows a 46-fold fluorescence enhancement in the presence of L-lactate, with an exceptional selectivity against a broad range of molecules and biological ions and metabolites. It enables specific detection of L-lactate in cancer cells, colorectal tumors, and diverse real samples, with excellent recoveries of 95.0%–110.0%. This strategy establishes a robust approach for endogenous small-molecule sensing and provides a versatile platform for biomedical applications.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Yanwei Wang,Jiahui Zhao,Yong Chen,Xuesong Liu,Tengfei Xu,Mingliang Fang
Chronic bisphenol exposure is a recognized disruptor of liver function, and although ferroptosis has been implicated, the underlying molecular mechanisms remain poorly defined. Here, integrative chemical proteomics and untargeted metabolomics were used to elucidate mechanisms of ferroptosis induced by bisphenol A (BPA) and bisphenol S (BPS) in hepatic cells. BPA elicited a pronounced ferroptotic phenotype, whereas BPS elicited a moderate phenotype in hepatocytes. Glutathione peroxidase 4 (GPX4) and pyruvate kinase M2 isoform (PKM2) were identified as critical targets, respectively. Validation through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and molecular docking confirmed that BPA specifically binds to GPX4 (KD = 37.6 μM), while BPS exhibits moderate affinity for PKM2 (KD = 14.4 μM). Functional rescue experiments demonstrated that GPX4 overexpression effectively reversed BPA-induced ferroptosis and partially alleviated BPS-induced effects, whereas PKM2 overexpression specifically mitigated BPS-triggered cytotoxicity. Mechanistically, BPA inhibited GPX4 activity, impairing lipid peroxide detoxification and triggering ferroptosis; BPS suppressed PKM2, promoting glucose flux toward the methylglyoxal (MGO) pathway, depleting glutathione, and activating oxidative stress, thereby inducing ferroptosis indirectly. This study clarifies bisphenol-induced ferroptosis via target heterogeneity, providing mechanistic insights that may inform future safety evaluations.
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ACS Sensors
·
2026
·
IF 9.1
Shaorui Qi,Lei Sun,Fansheng Meng,Guimei Shi,Yunlong Sun,Bo Jiang,Junbo Li,Yukihiro Ozaki,Wei Ji
Abnormal lactic acid (LA) enantiomeric excess (ee) in biofluids is closely associated with various intestinal diseases. Here, we report a chiral-label-free nonplasmonic surface-enhanced Raman scattering (SERS) platform using a ZIF-8/ZnS heterojunction that enables direct quantification of LA enantiomers and their ee values in raw human urine through a charge-transfer-driven chiral recognition mechanism. Our findings indicate that an enantioselective hydrogen bonding between 4-mercaptopyridine (4-MPy) probes and LA enantiomers induces differential charge-transfer effects within the ZIF-8/ZnS@4-MPy system, evidenced by the selective enhancement of specific vibrational modes in the SERS spectra of 4-MPy and enantiomer-specific changes in the fluorescence lifetime of ZnS. This innovative system integrates signal amplification and stereoselectivity without the use of noble metals or chiral modifiers, overcoming critical limitations associated with the complexity of preparing chiral plasmonic substrates. The platform achieves ultrasensitive detection limits (10 nM), linear response to ee values (R2 = 0.98), high measurement precision (RSD < 8.28%, n = 20), long-term stability (28-day), and clinical-grade accuracy against enzymatic assays (RMSEP = 1.97). This work presents an efficient, noninvasive method for the analysis of chiral metabolites in urine, while establishing a novel direction for plasmon-free SERS chiral sensing.
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JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
·
2022
·
IF 6.76
Jie Sun,Yaping Wang,Zhenguo Gao,Junbo Gong,Weiwei Tang
Herein, we report a successful resolution of L-norvaline, a racemic compound system, performed near the eutectic composition by coupling preferential crystallization with tailor-made additives. The structures of enantiomer and racemate were characterized by PXRD, DSC , and the enantiomeric purity were measured by Chiral HPLC. The preferential crystallization process was designed and established from binary melting phase diagram and ternary solution phase diagram. The effects of supersaturation, solution enantiomer composition, and seed quantity on the preferential crystallization process were investigated. However, the significant improvements of enantiomeric purity and product yield were demonstrated by additive-assisted preferential crystallization approach using tailor-made additives. These additives bearing similar structure motifs to norvaline a highly selective binding to the racemate rather than enantiomer and remarkably suppress nucleation of DL-norvaline, the key factor determining the resultant enantiomer purity and separation efficiency. The underly inhibition principle was revealed due to the centrosymmetric packing of the racemate while the polarity of enantiomer leads to only partial or slight crystallization suppression. The interesting inhibition mode by tailor-made additives is also believed to be applicable for other racemic crystallization systems. Our established additive-assisted preferential crystallization has showed great potential in the development of separation technology and resolution of enantiomer from racemic compounds.
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ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Xiao Zheng,Ying Liu,Yiqiong Liu,Tingting Zhang,Yuge Zhao,Jie Zang,Yan Yang,Ruiqing He,Gaowei Chong,Shuangrong Ruan,Dailin Xu,Yongyong Li,Haiqing Dong
Lactate accumulation in the solid tumor is highly relevant to the immunosuppressive tumor microenvironment (TME). Targeting lactate metabolism significantly enhances the efficacy of immunotherapy. However, lactate depletion by lactate oxidase (LOX) consumes oxygen and results in the aggravated hypoxia situation, counteracting the benefit of lactate depletion. Beyond the TME regulation, it is necessary to initiate the effective immunity cycle for therapeutic purposes. In this fashion, dual close-loop of catalyzed lactate depletion and immune response by a rational material design are established to address this issue. Here, we constructed PEG-modified mesoporous polydopamine nanoparticles with Cu2+ chelation and LOX encapsulation (denoted as mCuLP). After mCuLP nanosystems targeting into the tumor sites, released LOX consumes lactate to H2O2. Subsequently, the produced H2O2 is further catalyzed by Cu2+-chelated mPDA to produce oxygen, supplying the oxygen source for the closed-loop of lactate depletion. Meanwhile, the mild PTT caused by the photothermal mPDA induces ICD of tumor cells to promote DC maturation and then T lymphocyte infiltration to kill tumor cells, which forms another closed-loop for cancer immunity. Therefore, this dual closed-loop strategy of mCuLP nanosystems effectively inhibits tumor growth, providing a promising treatment modality to cancer immunotherapy.
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ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Jianjian Zhao,Aiyou Hao,Pengyao Xing
Developing efficient protocols to enhance the optical activities of chiral self-assemblies is a key to realizing their chiroptical functions such as chiral sensing and displays. Here, we have reported a coassembly protocol to efficiently boost the chiroptical responses, whereby the synthesis of chiroptical nanomaterials and highly accurate detection of enantiomeric excess (ee %) were achieved. A series of benzimidazole derivatives with different topologies underwent spontaneous aggregation and symmetry breaking in solution, generating silent Cotton effects, yet exclusive weak left-handed circularly polarized luminescence (CPL). The coassembly with natural hydroxyl acids via complementary H bonds afforded chiral nanostructures with emerged Cotton effects and enhanced CPL. Dissymmetry g-factors were dramatically boosted (glum from 1 × 10–3 to 5.5 × 10–2, gabs from 0 to 6.7 × 10–3). In addition, proof of concept of recognition and detection of natural chiral molecules was realized with high accuracy.
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NEUROPHARMACOLOGY
·
2020
·
IF 4.431
Kaiyang Ma,Xiao Ding,Qiqi Song,Zhitao Han,Hang Yao,Jianhua Ding,Gang Hu
In recent years, with the discovery and research of lactate-specific receptor HCAR1(hydroxycarboxylic acid receptor 1), lactate is not only as a product of Glycolysis in astrocytes, but also as a signaling molecule which has gradually received attention. Studies have found that lactate can be used as an intercellular signaling molecule involved in synaptic plasticity , and so that peripheral administration of lactate can produce antidepressant effects. Here, we focus on HCAR1 on the most widely distributed astrocytes in the brain, found and verified that lactate could cause Arc/arg3.1 protein overexpression in astrocytes through HCAR1. However, the expression of Arc/arg3.1 does not depend on the Gi protein pathway of HCAR1, and we found that lactate enhanced the expression of Arc/arg3.1 protein through the HCAR1-β-arrestin2 pathway. In summary, lactate acts on HCAR1 of astrocytes. It enhances the expression of MAPK-dependent Arc through β-arrestin2, thereby reducing the influx of calcium ions when astrocytes are exposed to glutamate damage, achieving the role of protecting astrocytes and indirectly enhancing the absorption of glutamate by astrocytes. These results also demonstrate that HCAR1 in the brain is a potential therapeutic target in an experimental in vitro model of glutamate damage, which is strongly associated with many neurodegenerative diseases .
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MOLECULES
·
2023
·Vol. 28
·期 12
·4723
·
IF 4.6
Rongxiu Qin,Haiyan Chen,Rusi Wen,Guiqing Li,Zhonglei Meng
To investigate the synergistic catalytic effects of boric acid and α-hydroxycarboxylic acids (HCAs), we analyzed and measured the effects of the complexation reactions between boric acid and HCAs on the ionization equilibrium of the HCAs. Eight HCAs, glycolic acid, D-(−)-lactic acid, (R)-(−)-mandelic acid, D-gluconic acid, L-(−)-malic acid, L-(+)-tartaric acid, D-(−)-tartaric acid, and citric acid, were selected to measure the pH changes in aqueous HCA solutions after adding boric acid. The results showed that the pH values of the aqueous HCA solutions gradually decreased with an increase in the boric acid molar ratio, and the acidity coefficients when boric acid formed double-ligand complexes with HCAs were smaller than those of the single-ligand complexes. The more hydroxyl groups the HCA contained, the more types of complexes could be formed, and the greater the rate of change in the pH. The total rates of change in the pH of the HCA solutions were in the following order: citric acid > L-(−)-tartaric acid = D-(−)-tartaric acid > D-gluconic acid > (R)-(−)-mandelic acid > L-(−)-malic acid > D-(−)-lactic acid > glycolic acid. The composite catalyst of boric acid and tartaric acid had a high catalytic activity—the yield of methyl palmitate was 98%. After the reaction, the catalyst and methanol could be separated by standing stratification.Keywords:boric acid;α-hydroxycarboxylic acid;ionization equilibrium;fatty acid esterification;green synthesis
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RSC Advances
·
2019
·Vol. 9
·期 16
·9006-9013
·
IF 3.049
Shengli Mi,Jingjing Xia,Yuanyuan Xu,Zhichang Du,Wei Sun
In this study, we developed an electrochemical microchannel biosensor platform to analyse lactate metabolism in cells. This biosensor platform was fabricated by photolithography, thin-film deposition and microfluidic technology. A kind of functional biomaterial was prepared by mixing lactate oxidase, single-walled carbon nanotubes and chitosan, and platinum as working and blank electrodes of the biosensor was modified by a thin Prussian blue layer. The lactate biosensor was obtained by dropping functional biomaterials on the electrode. The results demonstrated that the sensitivity of the electrochemical biosensor was up to 567 nA mM−1 mm−2 and the limit of detection was 4.5 μM (vs. Ag/AgCl as the counter/reference electrode). The biosensor used to quantitatively detect metabolic lactate concentrations in HepG2 cells cultured with cancer drugs showed high sensitivity, selectivity and stability, and has potential applications in organ-on-a-chip and tissue engineering technologies, which typically involve low concentrations of metabolites.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Qing Li,Congnan Wu,Jiaxing Zhang,Rongxin Su,Yuefei Wang,Wei Qi
The development of enantioselective nanozymes holds profound significance in synthesizing chiral compounds and elevating analytical precision. Herein, we have synthesized chiral gold/iron hierarchically organized particles (Cys@Au/Fe Hops) possessing peroxidase-like catalytic activity, through a one-pot method using cysteine as a chiral inducer. The nanozymes exhibited remarkable enantioselective catalytic activity to 3,4-dihydroxy-phenylalanine (DOPA) enantiomer. Notably, L -Cys@Au/Fe Hops, comprising right-handed helical nanopetals, exhibited elevated catalytic efficiency for L -DOPA over D -DOPA, whereas the reverse held for D -Cys@Au/Fe Hops. The molecular dynamics simulations demonstrated hydrogen bonding interactions between the active site and substrate, thereby revealing how steric effects affected the enantioselective catalysis of chiral DOPA by L/D -Cys@Au/Fe Hops. Moreover, the chiral nanozymes were developed into a test paper sensor due to their exceptional stability, which can achieve the visual detection of DOPA enantiomer combined with a smartphone platform. This work is significant in advancing the design and practical utility of highly selective enzyme mimics.
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