Correction: Zhuriheng pills improve adipose tissue dysfunction and inflammation by modulating PPARγ to stabilize atherosclerotic plaques

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Please confirm that the below Frontiers AI generated Alt-Text is an accurate visual description of your Figure(s). These Figure Alt-text proposals won't replace your figure captions and will not be visible on your article. If you wish to make any changes, kindly provide the exact revised Alt-Text you would like to use, ensuring that the word-count remains at approximately 100 words for best accessibility results. Further information on Alt-Text can be found here. Author's response related to adipocyte size, lipid droplets, protein expression, and BAT/eWAT analysis, with statistical comparisons. Zhuriheng pills improve adipose tissue dysfunction and inflammation by modulating PPARγ to stabilize atherosclerotic plaquesBackground: Adipose tissue Q7 dysfunction and chronic inflammation contribute to atherosclerosis plaque development. Zhuriheng pills (ZRH) are an effective Mongolian herbal formula used in treating coronary heart disease in China, but their mechanisms of action have not been fully elucidated. Purpose: To assess whether ZRH alleviates atherosclerosis (AS) and stabilizes plaque, this study investigates the modulatory effects of ZRH on AS and adipose tissue profiles in atherosclerotic model mice with vulnerable plaque to reveal the potential mechanisms and representative quality markers (Q-markers) of ZRH. Methods: In vivo, the vulnerable atherosclerotic plaque model was induced in ApoE -/-mice treated with intense co-stimulation. The anti-AS effect of ZRH was assessed by serum lipid profile, hematoxylin-eosin (HE), Oil O Red, Masson staining, immunohistochemistry (IHC), immunofluorescence, and plasma lipidomics. In vitro, a co-culture model was established with 3T3-L1 adipocytes treated with palmitic acid (PA) and RAW264.7 macrophages treated with lipopolysaccharide (LPS). The potential mechanism and Q-markers of ZRH were identified by lipid content test, inflammatory factors and adipocytokine analysis, flow cytometry for macrophage polarization, and Western blotting for PPARγ and UCP-1 proteins. Results: In vivo, ZRH stabilizes plaques by improving serum lipid profiles, lowering macrophage infiltration, and boosting collagen content in plaques. ZRH can counteract HFD-induced adipocyte hypertrophy, increase UCP-1 and PPARγ expression, enhance the "browning" of adipose tissue, and inhibit macrophage M1 polarization. Lipidomics results showed that ZRH treatment increased the abundance of lipid species with multiple unsaturated bonds and decreased harmful TAG, DAG, and HexCer. In addition, ZRH regulates inflammatory factors and adipokines in co-culture to inhibit macrophage M1 polarization and adipocyte abnormal lipid metabolism. In contrast, RDK and its monomers have a stronger anti-inflammatory effect, whereas GZ and its monomers regulate lipid metabolism better. ZRH was shown to be a PPARγ agonist for improving Atherosclerosis (AS) is a hallmark of atherosclerotic cardiovascular disease (ASCVD) and the major contributor to cardiovascular disease (CVD) mortality. AS is closely related to issues such as abnormal lipid dysregulation, chronic inflammation, and endothelial dysfunction. Acute cardiovascular events are mostly caused by thrombus from the erosion of vulnerable plaques (Libby and Hansson, 2019;Naghavi et al., 2003). Macrophages, the dominant immune cells within AS plaques, participate in multiple processes including the formation, progression, rupture, and healing of atherosclerotic plaques, via their plasticity of polarizing states and function (Hou P, et al., 2023). Furthermore, according to multiple studies, there is a positive correlation between coronary heart disease (CHD) risk and abnormal adipose tissue. In particular, inflammation, metabolic disorder, and the lowered "browning" thermogenic capacity of adipose tissue are directly linked to endothelial dysfunction and inflammatory cell infiltration in the blood vessels. As adipose tissue as a complex endocrine organ, excessive storage of triglycerides in fat tissue can trigger local and systemic inflammatory responses and interfere with the secretion of adipokines and macrophage polarization, thus further accelerating atherosclerosis development (Rigano et al., 2017;Singh et al., 2021;Mu W et al., 2021).Adipose tissue plays an important role in regulating whole-body energy metabolism through its storage function in white adipocytes (WAT) and its dissipating function in brown (BAT) and beige adipocytes (Kita et al., 2019). Dysfunctional adipose tissue promotes a pro-inflammatory, hyperlipidemic, and insulin resistant environment (Chait and den Hartigh, 2020). In adipose tissue, adipocytes and macrophages participate in the pro-inflammatory feedback cycle in adipose tissue, leading to chronic inflammation (Balakumar et al., 2019).Peroxisome proliferator-activated receptors (PPARs) are not only essential regulators of whole-body metabolism but also modulate inflammation in immune cells, notably macrophages (Lefere et al., 2020). PPARs include PPARα, PPARβ/δ, and PPARγ. Of these, PPARγ is mostly located in adipose tissue and the immune system; it is a crucial mediator between adipose tissue and atherosclerosis, controlling glucose and lipid metabolism, lipogenesis, and inflammatory response (Welch et al., 2022;Qian J and Sun Y, 2021). PPAR activators, such as PPARγ agonists, have been used for metabolic disorders and improving cardiovascular outcomes (Wang and Zhang, 2022).In China, the prescription of Zhuriheng drip pill (ZRH) originated from a Mongolian clinical formula for the treatment of cardiovascular diseases. The herbal medicine composition of ZRH includes Fructus Choerospondiatis (seed) (emperor, GuangZao, GZ), Myristica fragrans Houtt.(seed) (minister, RouDoukou, RDK), Lignum AquilariaeResinatum (ChenXiang, CX), Amomum Tsao-ko (CaoGuo, CG), asafetida (AWei, AW), Carthamus tinctorius L. (HongHua, HH), Gardenia jasminoides Ellis (ZhiZi, ZZ), synthetic borneol (BingPian, BP), and Bovis Calculus Artifactus (Artificial NiuHuang, NH) (Wang et al., 2018). In our previous studies, we used rapid high-performance liquid chromatographytandem quadrupole-electrostatic field orbitrap high-resolution mass spectrometry (HPLC-Q-Exactive-MS/MS) to identify 60 metabolites in ZRH, which were speculated in positive and negative ion modes (Zhang et al., 2024); 15 inherent metabolites were quantitatively analyzed (Bu et al., 2023). The network pharmacology, molecular docking, and spectrum-effect study of ZRH found that PPARs are the co-target of multiple metabolites which inhibit macrophage foaming by regulating the PPAR pathway (Zhai et al., 2024;Mu et al., 2019). However, despite ZRH efficacy in treating CHD, the molecular mechanisms and candidate Q-markers of ZRH towards CHD remain unclear.Therefore, this study aims to investigate the effects of ZRH on plaque stability and adipose tissue inflammation in AS. We established an ApoE -/-mouse model with atherosclerotic instability plaques (Ma et al., 2013) in vivo and a macrophage-adipocyte co-culture model in vitro to explore the underlying mechanisms of the ZRH. Our findings revealed that the ZRH pill positively impacted adipose tissue inflammation and plaque stability, validating the association between PPARγ regulation and ZRH. Meanwhile, we used an exclusion method to verify the role of the emperor and minister in prescription, improve the understanding of the compatibility mechanisms, and help identify the Q-markers of ZRH for CHD treatment. Fructus,Gardeniae Fructus,and Carthami Flos (18:6:8) was crushed to yield a powder and then extracted twice in 70% ethanol (1:10, mass to volume ratio) under reflux conditions for 2 h each. This extract was then filtered and concentrated to prepare a final concentration equivalent to 1.02-1.03 g/mL under reduced pressure. Next, synthetic borneol and Bovis Calculus Artifactus (ratio 1:1) were added. A mixture of Myristicae Semen, Ferulae Resina, Aquilariae Lignum Resinatum, and Fructus Tsaoko (12:2:2

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