Apigenin suppresses epithelial-mesenchymal transition in high glucose-induced retinal pigment epithelial cell by inhibiting CBP/p300-mediated histone acetylation.

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.

Paeoniflorin promotes PPARγ expression to suppress HSCs activation by inhibiting EZH2-mediated histone H3K27 trimethylation.

BACKGROUND: The alleviating effect of paeoniflorin (Pae) on liver fibrosis has been established; however, the molecular mechanism and specific target(s) underlying this effect remain elusive. PURPOSE: This study was to investigate the molecular mechanism underlying the regulatory effect of Pae on hepatic stellate cells (HSCs) activation in liver fibrosis, with a specific focus on the role of Pae in modulating histone methylation modifications. METHODS: The therapeutic effect of Pae was evaluated by establishing in vivo and in vitro models of carbon tetrachloride (CCl4)-induced mice and transforming growth factor ß1 (TGF-ß1)-induced LX-2 cells, respectively. Molecular docking, surface plasmon resonance (SPR), chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and other molecular biological methods were used to clarify the molecular mechanism of Pae regulating HSCs activation. RESULTS: Our study found that Pae inhibited HSCs activation and histone trimethylation modification in liver of CCl4-induced mice and LX-2 cells. We demonstrated that the inhibitory effect of Pae on the activation of HSCs was dependent on peroxisome proliferator-activated receptor γ (PPARγ) expression and enhancer of zeste homolog 2 (EZH2). Mechanistically, Pae directly binded to EZH2 to effectively suppress its enzymatic activity. This attenuation leaded to the suppression of histone H3K27 trimethylation in the PPARγ promoter region, which induced upregulation of PPARγ expression. CONCLUSION: This investigative not only sheds new light on the precise targets that underlie the remission of hepatic fibrogenesis induced by Pae but also emphasizes the critical significance of EZH2-mediated H3K27 trimethylation in driving the pathogenesis of liver fibrosis.

Applications of artificial intelligence in gastroscopy: a narrative review.

Gastroscopy, a critical tool for the diagnosis of upper gastrointestinal diseases, has recently incorporated artificial intelligence (AI) technology to alleviate the challenges involved in endoscopic diagnosis of some lesions, thereby enhancing diagnostic accuracy. This narrative review covers the current status of research concerning various applications of AI technology to gastroscopy, then discusses future research directions. By providing this review, we hope to promote the integration of gastroscopy and AI technology, with long-term clinical applications that can assist patients.

Si-Ni-San inhibits hepatic Fasn expression and lipid accumulation in MAFLD mice through AMPK/p300/SREBP-1c axis.

BACKGROUND: Soothing the liver and regulating qi is one of the core ideas of traditional Chinese medicine (TCM) in the treatment of fatty liver. Si-Ni-San (SNS) is a well-known herbal formula in TCM for liver soothing and qi regulation in fatty liver treatment. However, its efficacy lacks modern scientific evidence. PURPOSE: This study was aimed to investigate the impact of SNS on metabolic associated fatty liver disease (MAFLD) in mice and explore the underlying molecular mechanisms, particularly its effects on lipid metabolism in hepatocytes. METHODS: The therapeutic effect of SNS was evaluated using in vivo and in vitro models of high-fat/high-cholesterol (HFHC) diet-induced mice and palmitic acid (PA)-induced hepatocytes, respectively. Molecular biological techniques such as RNA-sequencing (RNA-seq), co-immunoprecipitation (co-IP), and western blotting were employed to elucidate the molecular mechanism of SNS in regulating lipid metabolism in hepatocytes. RESULTS: Our findings revealed that SNS effectively reduced lipid accumulation in the livers of HFHC diet-induced mice and PA-induced hepatocytes. RNA-seq analysis demonstrated that SNS significantly down-regulated the expression of fatty acid synthase (Fasn) in the livers of HFHC-fed mice. Mechanistically, SNS inhibited Fasn expression and lipid accumulation by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK). Activation of AMPK suppressed the activity of the transcriptional coactivator p300 and modulated the protein stability of sterol regulatory element-binding protein-1c (SREBP-1c). Importantly, p300 was required for the inhibition of Fasn expression and lipid accumulation by SNS. Furthermore, SNS activated AMPK by decreasing adenosine triphosphate (ATP) production in hepatocytes. CONCLUSION: This study provided novel evidence on the regulatory mechanisms underlying the effects of SNS on Fasn expression. Our findings demonstrate, for the first time, that SNS exerts suppressive effects on Fasn expression through modulation of the AMPK/p300/SREBP-1c axis. Consequently, this regulatory pathway mitigates excessive lipid accumulation and ameliorates MAFLD in mice.

First-principles study of thermodynamic stability and mechanical properties of fifteen high-entropy quaternary metal disilicides.

By combining first-principles density-functional calculations and thermodynamics, we investigated the thermodynamic stability and mechanical properties of 15 quaternary high-entropy metal disilicides composed of silicon and four of the six refractory transition metals Ti, Zr, Hf, V, Nb, and Ta. We constructed a three-dimensional diagram specified by two thermodynamic parameters (the mixing enthalpy and the ratio of the entropy term in the Gibbs free energy to enthalpy) and a structural parameter (the lattice size difference). The obtained diagram allows us to predict that, except for TiZrHfVSi8, the formation of all other fourteen single-phase metal disilicides is thermodynamically favorable. Our calculations show that, for the formation of each of the 14 metal disilicides, the driving force suppresses the resistance at temperatures well below the melting point, suggesting that it is feasible to synthesize these high-entropy materials. One of these (TiHfNbTaSi8) has already been experimentally realized. Furthermore, the values of the mechanical parameters and melting points of the predicted fourteen quaternary high-entropy metal disilicides are all greater than the corresponding average values of the four single-metal disilicides.

Two-Step Melting in a Bulk Crystal via Intermediate Metastable Liquid.

The mechanism of melting is significant, as it links the structure and dynamics between crystal and liquid. In two dimensions, the crystal could first melt into a hexatic liquid before finally reaching a disordered liquid. However, such a hexatic liquid phase is unstable in three dimensions, and melting is recognized as a one-step process. Here we report a two-step melting process in a three-dimensional system, (S)-(+)-ibuprofen. The crystal melts through an indirect pathway that first transforms into an intermediate liquid phase exhibiting an extremely long lifetime followed by the transition to the ordinary liquid phase at a spinodal point with the occurrence of long-range fluctuations. Such observations suggest that the complexity of liquid could affect the transition pathway of melting. These results could lead us to hypothesize the existence of continuous melting in three dimensions.

[Research and application of intelligent hyperspectral analysis technology for Chinese materia medica].

With the development of imaging technology and artificial intelligence, hyperspectral imaging technology provides a fast, non-destructive, intelligent, and precise new method for the analysis of Chinese materia medica(CMM). This paper summarized the methods and applications of hyperspectral imaging technology combined with intelligent analysis technology in the field of CMM in recent years, focusing on the acquisition and preprocessing of hyperspectral data, intelligent analysis methods of hyperspectral data, and practical cases of these technologies in the field of CMM. Hyperspectral data of CMM can provide spectral information with nanometer-level resolution and rich spatial texture information simultaneously. This paper summarized the acquisition process, including black-and-white board calibration and region-of-interest extraction, and preprocessing methods including smoothing, differentiation, scale-space, and scattering correction. The feature extraction methods in terms of spectral, spatial, color, and texture were briefly described, and common modeling methods were summarized. Finally, this paper reviewed the research cases of the application of the above methods to the fields of CMM, such as authenticity identification, origin tracing, variety recognition, year identification, sulfur fumigation degree determination, and quantitative measurement.

Hydrogenation Effect on Interlayer Coupling and Magneto-Transport Properties of Pd/Co/Mg/Fe Multilayers.

Hydrogenation-induced modification of magnetic properties has been widely studied. A Mg spacer layer with high hydrogen storage stability was clamped in a Pd/Co/Mg/Fe multilayer structure to enhance its hydrogen storage stability and explore the structure's magneto-transport properties. After 1 bar hydrogen exposure, the formation of a stable MgH2 phase was demonstrated in an ambient environment at room temperature through X-ray diffraction. Lower magnetic coupling and enhanced magnetoresistance, compared to those of the as-grown sample, were observed using the longitudinal magneto-optical Kerr effect and a four-probe measurement. In this study, the hydrogenation stability of ferromagnetic multilayers was improved, and the concept of a hydrogenation-based spintronic device was developed.

First-principles investigation of stable lead-free halide perovskite materials CsSnClxBryI3-x-yfor solar cell applications.

Perovskite solar cells based on hybrid organic-inorganic lead halide materials have attracted immense interest in recent years due to their enhanced power conversion efficiency. However, the toxic lead element and unstable property of the material limit their applications. With first-principles calculations based on density functional theory, we studied a series of ten lead-free perovskite materials made of cesium, tin, and halogen elements, chlorine (Cl), bromine (Br), and iodine (I). We found that the relative concentrations of the halogen atoms determine the crystal structures and the relative stability of the halide perovskites. Chlorine tends to increase the structural stability, while iodine plays the role of reducing the band gaps of the mixed halide perovskites. Considering the stability and the requirement of suitable band gaps, we identify that, among the ten lead-free halide perovskites, CsSnCl2I, CsSnBr2I, CsSnClBrI, CsSnClI2, CsSnBrI2, and CsSnI3are the appropriate choices for solar cell applications.

Experimental evidence of ß-relaxation and its structural origin in ZIF-62 glass.

Intrinsic relaxation processes determine the crucial properties of glass, yet their underlying mechanisms are far from well understood. The brand-new glass-forming metal-organic frameworks (MOFs) provide desirable opportunities for looking inside glass relaxation, especially the secondary ß-relaxation phenomenon and mechanism. For a representative zeolitic imidazolate framework-62 (ZIF-62) glass, reliable and fine powder mechanical spectroscopy was performed based on home-made mountings combined with a commercial dynamical mechanical analyzer. For the first time, ß-relaxation was observed in a MOF glass besides the primary α-relaxation. The pronounced ß-relaxation was well demonstrated by a number of characteristics including an excess wing and the full width at half maximum (W) of the α-relaxation peaks, which deviated from the time-temperature superposition. The stretched exponent ß of ZIF-62 glass is 0.71 in the supercooled region. The W of ZIF-62 glass is the maximum among all known glassy materials. The structural origin of α- and ß-relaxation can be attributed to an increase of density, as observed using nuclear magnetic resonance (NMR). A general linear and broad correlation of fragility and stretched exponent ß with W of the α-relaxation peaks was established. When compared with traditional glass-formers, the resulting principles indicate a shared origin for the stretched exponent ß, W, and ß-relaxation in the case of ZIF-62 glass. The presented findings offer an effective new method to explore the glass/liquid transition of MOF glasses, which helps to obtain a deeper insight into the hierarchical relaxation dynamics of the glass transition.

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1.

Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.

Runoff effect of precipitation variation and landscape pattern evolution in Lianshui watershed, Jiangxi, China.

Precipitation and landscape pattern are two main factors affecting runoff process of the watershed. Understanding their runoff effect is of great significance to water resources management and ecological construction of watershed. Based on the data of precipitation, runoff, and land use from 1958 to 2020, we analyzed the characteristics of precipitation, landscape pattern and runoff in Lianshui watershed in red soil hilly area of southern Jiangxi Pro-vince, established the relationship between precipitation, landscape pattern and annual runoff, flood runoff, low runoff, respectively. The results showed that the annual precipitation, runoff and annual maximum one-day runoff in the watershed showed a non-significant downward trend during the study period, while the annual minimum one-day runoff showed a non-significant upward trend but with the largest inter-annual variation range. Forested land was the landscape type with the highest proportion in watershed, and other woodland had the most dramatic variation. At the landscape level, Shannon diversity index, Shannon evenness index, patch density and landscape shape index increased from 1.125, 0.541, 0.667 and 16.925 in 1980 to 1.348, 0.614, 0.731 and 18.172 in 2020, respectively, while the landscape contagion index decreased from 68.237 in 1980 to 64.293 in 2020. The overall landscape diversity, fragmentation degree and shape complexity of the watershed increased, the spatial distribution tended to be uniform, and the connectivity decreased. The correlation coefficients between precipitation and annual runoff, flood runoff, low runoff were 0.907, 0.594 and 0.558, respectively. At the class level, the reduction of cultivated land had a greater impact on annual runoff, flood runoff, and low runoff, while the overall change at the landscape level promoted a decrease in annual runoff and flood runoff and an increase in low runoff. The contribution rate of precipitation variation and landscape pattern evolution to the change of annual runoff, flood runoff ,and low runoff were 17.8%, 82.2% and 1.5%, 98.5% and -8.8%, 108.8%, respectively. Our results could provide theoretical refe-rence for landscape pattern allocation and comprehensive management of soil and water loss.

An enzyme activated fluorescent probe for LTA4H activity sensing and its application in cancer screening.

Early diagnosis of cancer is an efficient strategy to prevent tumor progression and improve the survival rate of patients. However, to discovery of reliable tumor-specific biomarkers remains a great challenge. Leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc metalloenzyme with epoxide hydrolase activity and aminopeptidase activity, which plays important roles in allergic and inflammatory reactions and showed strong relevance with carcinoma progression. We thus sought to investigate the possibility of application LTA4H activity detection in cancer diagnosis. To achieve this, we herein develop an enzyme activated fluorescent probe for LTA4H activity sensing by incorporating the specific recognition unit of LTA4H with a red-emitting fluorophore. The acquired probe (named as ADMAB) showed high sensitivity and specificity toward LTA4H in vitro. By further application of ADMAB in living cells, significantly elevated LTA4H activity in cancer cell lines was observed when compared with normal cell lines and in vivo tracing A549 tumor in nude mice was also realized by ADMAB. Meanwhile, the wound-healing assay further revealed the importance of LTA4H in tumor metastasis. Moreover, the LTA4H activity in human serum sample was successfully detected by ADMAB and significantly elevated LTA4H activity in patients diagnosed with cancer was firstly found, which demonstrated ADMAB to be a useful tool for cancer diagnosis and LTA4H related biological study.

De Novo Design of a Highly Selective Nonpeptide Fluorogenic Probe for Chymotrypsin Activity Sensing in a Living System.

Chymotrypsin, an extensively known proteolytic enzyme, plays a substantial role in maintaining physiological functions, including protein digestion, immune response, and tissue repair. To date, intense attention has been focused on the invention of efficient and sensitive chemical tools for chymotrypsin activity measurement. Among them, the "nonpeptide"-based chymotrypsin probe design strategy utilizing the esterase activity of chymotrypsin has been well-developed due to its low cost and high atom-economy feature. However, the ester-bond-based nature of these probes make them possibly vulnerable to esterases and active chemicals. These defects strictly restricted the application of the previously reported probes, especially for imaging in living systems. Therefore, to acquire fluorogenic probes with sufficient stability and specificity for chymotrypsin sensing in a complicated biological environment, a more stable skeleton for nonpeptide-based chymotrypsin probe construction is urgently needed. Herein, a novel nonpeptide-based fluorogenic probe for specific chymotrypsin activity sensing was designed and synthesized by the substitution of an ester-based linker with a heptafluorobutylamide moiety. The acquired probe, named TMBIHF, showed high selectivity toward various enzymes and reactive chemicals, while it retained high sensitivity and catalytic efficiency toward chymotrypsin. Moreover, TMBIHF was successfully applied for monitoring chymotrypsin activity and pancreas development in live zebrafish, specific sensing of exogenous and endogenous chymotrypsin in nude mice, and visualizing chymotrypsin-like activity-dependent cellular apoptosis, thus providing an alternative and reliable way for chymotrypsin-targeted biosensor or prodrug construction.

A highly sensitive and selective enzyme activated fluorescent probe for in vivo profiling of carboxylesterase 2.

Carboxylesterase 2 (CES2) is a serine-type hydrolase that plays important roles in xenobiotic detoxification and lipid metabolism. Its abnormal expression is highly associated with diseases such as diabetes and carcinoma. To date, intense attention has been attracted to CES2 targeted drug discovery and disease diagnosis. Thus, to further explore the physiological function of CES2 is of great importance. However, until now, most medical research on CES2 function and activity assays is still dependent on conventional methods, which could hardly specify CES2 activity. Therefore, there is an urgent need to develop efficient tools for selective measurement and sensing of endogenous CES2 in complicated biological system. In this study, we report the design and construction of an enzyme-activated fluorescent probe for CES2 activity sensing. The acquired probe DXMB was characterized as a highly specific and sensitive fluorescent probe for CES2 and possessed superior binding affinity, overall catalytic efficiency, and reaction velocity when compared with the reported CES2 probes. By application of DXMB into living system, it was capable of sensing endogenous CES2 in living cells, dynamic monitoring CES2 in zebrafish development, and visualizing tissue distribution of CES2 in nude mice. Most importantly, abnormally elevated CES2 activity in the intestine of diabetic model mice was first revealed, while significantly decreased CES2 activity in the liver was validated by DXMB. These results indicated that DXMB could serve as a vital tool for further CES2-related biological and medical research.

[Baseflow variation and its response to precipitation in Jiuqushui watershed, Southern Jiangxi Province, China]. / èµ£å—ä¹æ›²æ°´æµåŸŸåŸºæµå˜åŒ–ç‰¹å¾åŠå ¶å¯¹é™æ°´çš„å“åº”.

Baseflow is an important part of water resources. Exploring the characteristics of baseflow and its response to precipitation is of great significance to optimize the partition of water resources. Based on the data of daily precipitation and runoff from 1982 to 2019 in Jiuqushui watershed, we analyzed the characteristics of baseflow change, investigated the time lag effect of baseflow on precipitation, and calculated the contribution rate of precipitation to baseflow change by using digital filtering method, cross wavelet transform method, and slope change ratio of accumulative quantity method. The results showed that during the study period, the variation trend of annual baseflow depth and annual baseflow index was not significant, with annual average values of 384.21 mm and 0.44, respectively. The depth of baseflow in spring and summer was greater than that in autumn and winter, while the baseflow index showed an opposite pattern. Annual precipitation affected the dynamic change of annual baseflow depth, with the effects in spring and summer being stronger than that in autumn and winter. The lag time of baseflow in spring, summer, autumn and winter were 3.5-10.3, 1.5-8.5, 2-10, 2-13 and 5-20.5 days, while the average annual lag time was 6.4, 4.9, 5.3, 6.8 and 10.8 days, respectively. The annual baseflow depth changed abruptly in 1992. The contribution rate of precipitation to baseflow change was 68.2%, and that of other factors was 31.8%. The results could provide scientific basis for evaluating the hydrological effects of forests and ensuring water ecological security of rivers in the red soil region of southern China.

Modifications decrease hepatic steatosis in Taiwanese with metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) is a growing global problem associated with increasing obesity prevalence. Lifestyle modifications are currently recommended, including weight reduction, exercise, and diet control. This study evaluated the short-term effect of lifestyle modifications on transient elastography (TE) values in an obese population with MAFLD. Thirty-two MAFLD patients were recruited for this prospective study and all subjects participated in a 3-month program of lifestyle modification. Sequential demographic parameters and biochemical tests were compared before and after program completion. Liver fat and fibrosis changes were measured using TE with controlled attenuated parameter (CAP) and liver stiffness measurements (LSM). The mean age was 38.7 years old (10 males). The body weight (88.09 kg vs. 80.35 kg), body mass index (32.24 kg/m2 vs. 29.4 kg/m2 ), waist (103.19 cm vs. 95.75 cm), and hip circumference (111.67 cm vs. 104.75 cm), and blood pressure (128/78 mmHg vs. 119/71 mmHg) significantly improved before and after the intervention, respectively. Aspartate aminotransaminase (24.06 U/L vs. 18.91 U/L), alanine aminotransaminase (33 U/L vs. 23.72 U/L), creatinine (0.75 mg/dl vs. 0.70 mg/dl), cholesterol (176.41 mg/dl vs. 166.22 m/dl), gamma-glutamyl transferase (26.59 IU/L vs. 19.81 IU/L), and low-density lipoprotein cholesterol (115.63 mg/dl vs. 103.19 mg/dl) also improved after the 3-month intervention. The average CAP significantly decreased after intervention (297.5 dB/m vs. 255.0 dB/m), however, no significant difference in LSM was observed (5.24 kPa vs. 4.82 kPa). The current study suggests that short-term lifestyle modification can effectively improve hepatic steatosis, and TE may serve as a monitoring tool for therapeutic intervention.

PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer.

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non-tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down-regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/ß-catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion, in vitro and in vivo data demonstrate that PCNP as a tumor suppressor gene may serve as a novel prognostic and potential therapeutic marker in human thyroid cancer.

The antihyperlipidemic equivalent combinatorial components from peel of Citrus reticulata 'Chachi'.

Since the combinatorial components responsible for the antihyperlipidemic activity of Citrus reticulata 'Chachi' (CRC) peels remains unclear, we herein developed a bioactive equivalence oriented feedback screening method to discover the bioactive equivalent combinatorial components (BECCs) from CRC peels. Using palmitic acid (PA)-stimulated hepatocyte model, a combination of 5 polymethoxyflavones (PMFs) including tangeretin, sinensetin, nobiletin, 5,7,8,4'-tetramethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone was identified to be responsible for the antihyperlipidemic effect of CRC peels. Via evaluation of combination effect by combination index (CI), these 5 PMFs were found to take effect via a synergistic mode. Our data indicated that the antihyperlipidemic mechanism of PMF combination was associated with the inhibition of fatty acid and cholesterol synthesis, and inflammation. Also, the PMF combination exhibited robust antihyperlipidemic effects in HFD-fed rats in vivo. Our study offers evidence-based data to uncover the pharmacological effect of CRC peels.