Jin Hyup Lee

Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates detoxification and antioxidant programs that protect the liver from chemical and metabolic stress. Nrf2 is restrained by Kelch-like ECH-associated protein 1 (Keap1), which can be removed through p62-mediated selective autophagy; however, nutritional cues that engage this pathway remain incompletely understood. This study provides evidence that betaine (trimethylglycine; BET) can regulate the Keap1-Nrf2 axis through modulation of Keap1. In biochemical and cellular assays, betaine was associated with methylation of Keap1 at Cys513 and Cys518 within the Kelch domain, which was linked to enhanced p62-dependent autophagic degradation of Keap1 and Nrf2 stabilization. In AML12 hepatocytes and in mice, betaine enhanced Nrf2 activity, induced canonical Nrf2 target genes, and increased cellular glutathione (GSH), consistent with improved GSH-dependent redox capacity. In an acetaminophen (AAP) overdose model, betaine attenuated hepatic injury, consistent with improved redox capacity under acute toxic stress. In an MCD diet-induced steatotic liver disease model, betaine was associated with reduced steatohepatitis-like histopathology, inflammatory signaling, and lipogenic markers. Finally, RNA-seq analysis of a large human metabolic dysfunction-associated steatotic liver disease (MASLD) cohort revealed Nrf2-related transcriptomic signatures associated with disease severity, providing correlative support for the disease relevance of this pathway. Collectively, these findings suggest that Keap1 cysteine methylation may represent a regulatory node linking betaine to p62-mediated autophagy, Nrf2 stabilization, and GSH homeostasis, while further studies are required to establish the causal and translational relevance of this mechanism in human liver disease.

Obesity, characterized by excessive fat accumulation, poses global health risks due to its association with metabolic diseases. Beyond conventional treatments, the gut microbiome has emerged as a promising therapeutic target. Given the critical role of microbiome alterations in obesity, modifying its composition through probiotics, prebiotics, or synbiotics offers a novel strategy for mitigating obesity and related conditions. In this study, we demonstrate the dose-dependent anti-obesity effects of a novel strain, Bifidobacterium longum subsp. longum HN001 (HN001), in a high-fat diet (HFD)-induced mouse model. Among the doses tested (100, 200, and 400 mg/kg), the 200 mg/kg dose showed the most pronounced effect, significantly reducing body weight gain, serum triglyceride (TG), and total cholesterol (TC) levels. These effects were associated with reductions in fat mass and adipocyte hypertrophy in white adipose tissue (WAT), suppression of lipogenesis, and enhanced energy expenditure through WAT browning and thermogenesis in brown adipose tissue (BAT). Microbiome analysis revealed that HN001 increased the abundance of beneficial, SCFA-producing microbes while reducing taxa linked to metabolic dysfunction. Importantly, HN001 restored serum short-chain fatty acid (SCFA) levels, and its lipid-lowering effect in adipocytes was attenuated by a GPR43 antagonist, supporting an SCFA–GPR43–mediated pathway that links microbiome modulation with reduced adipogenesis and enhanced thermogenesis. These findings suggest that HN001 may represent a promising therapeutic strategy for obesity via SCFA-driven modulation of host metabolism and gut microbiome composition.

Enabling the precise control of protein functions with artificially programmed reaction patterns is beneficial for investigating biological processes. Although several strategies have been established that employ the programmability of nucleic acid, they have been limited to DNA hybridization without external stimuli or target binding. Here, we report an approach for the DNA-mediated control of the tripartite split-GFP assembly via aptamers with responsiveness to intracellular small molecules as stimuli. We designed a novel structure-switching aptamer-peptide conjugate as a hetero modulator for split GFP in response to ATP. By conjugating two peptides (S10/11) derived from the tripartite split-GFP to ATP aptamer, we achieved GFP reassembly using only ATP as a trigger molecule. The response to ATP at ≥4 mM concentrations indicated that it can be applied to respond to intracellular ATP in live cells. Furthermore, our hetero-modulator exhibited high and long-term stability, with a half-life of approximately four days in a serum stability assay, demonstrating resistance to nuclease degradation. We validated that our aptamer-modulator split GFP was successfully reconstituted in the cell in response to intracellular ATP levels. Our aptamer-modulated split GFP platform can be utilized to monitor a wide range of intracellular metabolites by replacing the aptamer sequence.

This study aimed to determine the optimal combination of three anti-inflammatory materials [i.e., Cervus nippon Temminck (CT), Angelica gigas Nakai (AN), and Rehmannia glutinosa (RG)] for the strongest anti-inflammatory potential. Eighteen combinations of the three materials were tested in LPS-stimulated RAW264.7 cells via assessing nitric oxide (NO). The best combination from in vitro studies was administered to LPS-treated C57BL/6J mice for five days. Subsequently, plasma metabolites were profiled by bioinformatics analyses and validations. As results, 2, 20, and 50 µg/mL of CT, AN, and RG (TM) were the most effective combination suppressing inflammation. In mice, TM mitigated hepatic inflammatory markers. Similarly, the metabolomics indicated that TM may suppress NF-κB signaling pathway, thereby alleviating hepatic inflammation. TM also decreased systemic and hepatic pro-inflammatory cytokines. Collectively, we found the optimal combination of TM for mitigating inflammation; thus further studies on safety, mechanisms, and clinical models are warranted for human applications.

The direct effects of particulate matter (PM) on lung injury and its specific molecular mechanisms are unclear. However, experimental evidence has shown that oxidative stress-mediated inflammation in macrophages is the main pathological outcome of PM exposure. Curcumin has been reported to protect organs against the disturbance of homeostasis caused by various toxic agents through anti-inflammatory and antioxidative effects. However, the protective action of curcumin against PM-induced pulmonary inflammation and the underlying mechanism have not been thoroughly investigated. In this study, we established a PM-induced pulmonary inflammation mouse model using the intratracheal instillation method to investigate the protective ability of curcumin against PM-induced pulmonary inflammation. Compared to the mice treated with PM only, the curcumin-treated mice showed alleviated alveolar damage, decreased immune cell infiltration, and reduced proinflammatory cytokine production in both lung tissue and BALF. To evaluate the underlying mechanism, the mouse macrophage cell line RAW264.7 was used. Pretreatment with curcumin prevented the production of PM-induced proinflammatory cytokines by deactivating NF-κB through the suppression of MAPK signaling pathways. Furthermore, curcumin appears to attenuate PM-induced oxidative stress through the activation of Nrf2 and downstream antioxidant signaling. Our findings demonstrate that curcumin protects against PM-induced lung injury by suppressing oxidative stress and inflammatory activation in macrophages.