OBJECTIVE:This study aimed to investigate the multi-target mechanisms of Glabrone, an isoflavonoid derived from licorice, in the treatment of ulcerative colitis (UC), focusing on its synergistic effects in mucosal barrier repair and inflammation suppression. METHODS:The therapeutic effects of Glabrone were assessed in 3 % DSS-induced UC mice model. Evaluations included disease severity, histopathological damage, inflammatory cytokine levels, and intestinal barrier integrity. The anti-inflammatory activity of Glabrone was further examined in LPS-stimulated NCM460 and RAW264.7 cells. Potential targets were predicted using network pharmacology and molecular docking and subsequently validated through experimental approaches. Preliminary in vivo safety was also evaluated. RESULTS:Glabrone administration significantly alleviated UC symptoms, as indicated by reduced disease activity index, restored colon length, and improved histopathological changes. It demonstrated synergistic therapeutic effects by enhancing the mucosal barrier through upregulation of tight junction proteins (ZO-1, Occludin-1, and Claudin-1) and increased goblet cells, while simultaneously suppressing inflammation via reduction of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Furthermore, Glabrone was found to target SRC and HSP90, inhibit PI3K-Akt pathway, and activate p53 and estrogen receptor signaling pathways. Critically, Glabrone effectively antagonized SRC activation induced by MSI-1436, providing evidence for SRC as a key therapeutic target. This co-modulation of SRC/HSP90 underpins its multi-target action. Importantly, Glabrone showed no significant toxicity in vivo. CONCLUSION:Glabrone ameliorates UC through coordinated modulation of SRC/HSP90, which synergistically promotes mucosal barrier restoration and suppresses inflammatory responses. These results provide theoretical basis for developing Glabrone as a candidate multi-target therapeutic agent for UC.

Selenylation is known to enhance polysaccharide bioactivity, yet its potential to specifically improve the antimelanogenic performance of Cinnamomum cassia (C. cassia) polysaccharides remains underexplored. In this study, fraction CCP1 was identified as the most effective of the five fractions purified from C. cassia and was subsequently subjected to selenylation to yield Se-CCP1 (Se content: 862.7 mu g/g). Structural analyses confirmed that selenylation successfully introduced Se-C and Se--O bonds while preserving the polysaccharide backbone. Critically, this modification optimized physicochemical properties by reducing particle size (from 472.2 nm to 221.1 nm) and increasing the absolute zeta potential, thereby enhancing solubility and stability. Consequently, Se-CCP1 exhibited markedly superior anti-melanogenic efficacy compared to native CCP1. In zebrafish and B16 melanoma cells, Se-CCP1 achieved melanin inhibition comparable to that of CCP1 at significantly lower concentrations. Mechanistic investigation revealed that this enhanced activity was attributed to the potent suppression of the CREB/MITF/tyrosinase pathway. These results demonstrated that selenylation optimized both the structure and bioactivity of cinnamon polysaccharide, positioning Se-CCP1 as a highly efficient candidate for anti-hyperpigmentation therapy.

Abnormal skin pigmentation is one of the most common skin conditions worldwide. The search for safe, effective, and well-tolerated skin-whitening agents remains a major challenge for the pharmaceutical and cosmetics industries. Glabridin, often referred to as the “whitening gold”, is widely recognized as one of the most potent natural skin-whitening ingredients. However, its low bioavailability, poor skin permeability, and poor stability severely limit its efficacy in conventional topical formulations. In this study, we propose using glycyrrhizic acid to encapsulate glabridin, employing a “combined excipient and active ingredient” approach to improve the solubility, water dispersibility, and stability of glabridin, thereby enhancing its transdermal delivery efficiency. The micelles also inhibit melanin production and reduce tyrosinase activity. Compared with simple physically mixed solutions or glabridin used alone, these micelles significantly inhibited the expression of the TYR, TRP-1, and TRP-2 genes; downregulated the expression of α-MSH, cAMP, and MITF; and downregulated BMAL1 expression whilst upregulating PER1 expression. This study demonstrates that glycyrrhizic acid-glabridin micelles exert a synergistic effect by simultaneously targeting classical skin-whitening pathways and circadian regulatory networks, indicating great potential for skin whitening and providing a new strategy for developing novel, highly effective skin-whitening agents.

The interplay between nutrient availability and arbuscular mycorrhizal fungi (AMF) symbiosis during plant growth exhibits intricate complexity. In this study, we employ integrated physiological, transcriptomic, proteomic, and metabolomic analyses to investigate how sugarcane differentially adapts to nitrogen (N) fertilization and AMF colonization. Under nitrogen stress conditions, AMF colonization significantly enhances sugarcane growth, increasing plant height, stem diameter, and biomass while stimulating root exudation and rhizospheric nutrient mobilization-particularly available N, phosphorus (P), and potassium (K). Multi-omics analyses reveal that AMF induces nitrogen-dependent metabolic reprogramming in sugarcane roots, activating pathways such as carbohydrate and lipid metabolic pathways while suppressing butanoate and ascorbate metabolism. Weighted gene co-expression network analysis (WGCNA) identifies key root modules strongly correlated with soil N, P, and K availability, indicating AMF-mediated coordination of nutrient acquisition strategies. Field trials demonstrate that AMF boost sugarcane yield under nitrogen stress by enhancing root elongation and carbon partitioning for sucrose accumulation. Temporal integration of transcriptomic and metabolomic data highlights flavonoid biosynthesis as a persistently activated pathway across growth stages, potentially facilitating AMF symbiosis and stress resilience. Our findings elucidate how sugarcane optimizes AMF-mediated nutrient acquisition under nitrogen stress through root transcriptional and metabolic adjustments, providing insights for sustainable crop nutrient management.

IntroductionConventional polyethylene (PE) mulch causes persistent soil plastic pollution; biodegradable mulch films (BMFs) may avoid this, but their effects on sugarcane rhizosphere microbes and yield are unclear.MethodsUsing a field trial in Yunnan, we compared polyethylene mulch (PM) with two PBAT/PLA-based biodegradable mulch films (BMFs) differing in thickness (Thick Film, BTK, 0.008 mm; Thin Film, BTH, 0.005 mm). Rhizosphere soil (0–40 cm) physicochemical properties, bacterial (16S) and fungal (18S) communities, predicted microbial functional potentials, and sugarcane agronomic traits were analyzed.ResultsBMFs degradation released organic carbon that significantly altered the rhizosphere microenvironment, increasing soil pH, organic matter, and available potassium relative to PM. These physicochemical changes drove microbial community differentiation. Compared with PM, BMFs increased the relative abundances of Chloroflexi, Acidobacteria, and Basidiomycota, while decreasing Actinobacteria and Ascomycota (p < 0.05). BMFs also enhanced microbial α-diversity, with bacterial diversity being higher under BTK and fungal diversity under BTH. Neutral model analysis revealed that bacterial community assembly was dominated by stochastic processes; however, BMFs reduced dispersal limitation and strengthened deterministic environmental filtering, particularly under the BTH treatment, due to enhanced microhabitat heterogeneity from faster degradation. These community shifts were associated with enriched predicted sulfur (dsrAB) and nitrogen (nosZ, nif) cycling genes and more complex, cooperative bacterial–fungal interaction networks, with BTH exhibiting higher network complexity and positive interactions. These microbial responses were associated with improved sugarcane performance. Compared with PM, BMFs increased single stalk weight by 8.76%−11.68%, millable stalk number by 4.99%−7.38%, and cane yield by 17.11%−17.40%.DiscussionCollectively, our results demonstrate that BMFs, through degradation-driven microhabitat alteration, strengthen deterministic assembly, promote functionally specialized taxa and cooperative networks, and enhance predicted nutrient cycling potentials, thereby improving sugarcane productivity and offering a sustainable alternative to PE mulch.

Two homogeneous polysaccharides, PFSP-1 and PFSP-3, were isolated from perilla (Perilla frutescens L.) seeds (PFSP) and exhibited significant structural differences. Molecular weights of PFSP-1 and PFSP-3 were 3.58 & times; 104 Da and 1.04 & times; 107 Da, respectively. Monosaccharide composition analysis indicated that PFSP-1 consisted of fucose, glucose, and galactose in a molar ratio of 1.36:1.94:1, whereas PFSP-3 was composed of fucose, xylose, glucose, and galactose at a ratio of 3.63:1.21:19.62:1. Morphological observations revealed that PFSP-1 displayed irregular flocculent formations with smooth surfaces, while PFSP-3 showed continuous sheet-like structures. A comparison of bioactivity revealed that PFSP-1, but not PFSP-3, significantly inhibited the proliferation of HCT-116 colon cancer cells. PFSP-1 potently induced apoptosis as evidenced by increased TUNEL positivity, caspase-9/3 activation, and mitochondrial membrane potential collapse. Transcriptomics and validation identified BID and BAX as key mediators. Further validation confirmed that PFSP-1 promoted BID expression, facilitated BAX activation, and triggered mitochondrial dysfunction, ultimately leading to the execution of apoptosis via the caspase-9/caspase-3 cascade. These findings collectively demonstrate that structural variations, particularly in monosaccharide composition and molecular architecture, critically govern the differential anti-colon cancer activity of perilla seed polysaccharides.

INTRODUCTION:The aim of this study is to investigate the active material basis and action mechanism of BYD in spleen deficiency. METHODS:First, to study the therapeutic effect of BYD on spleen deficiency, a spleen deficiency mice model was established by injected reserpine. Then, the UPLC-QTOF-MS/MS was used to analyze the chemical composition characteristics of BYD formula particles and the blood-absorbed constituents. Next, the correlation network between the blood-absorbed constituents of BYD formula particles and spleen deficiency was established, and the action mechanism of the key active components was confirmed by KEGG enrichment analysis. Finally, the mechanism of action was verified by Western blot and Real time Quantitative PCR experiments. Apart from that, the in vivo safety of BYD formula particles was evaluated by toxicological experiments. RESULT:BYD formula particles significantly improved weight loss, restored immune organ index, and inhibited inflammation in mice with spleen deficiency. 249 active ingredients were identified in BYD formula granules, of which 47 could be absorbed by bloodstream such as Liquiritigenin, Wogonoside, Isoliquiritigenin and Oroxylin A-7-O-β-D-glucuronide, they were considered as the key active ingredients in BYD treatment for spleen deficiency. Network pharmacology analysis found that BYD mainly treated spleen deficiency by regulating apoptosis and angiogenesis. BYD upregulated Bcl-2, downregulated Bax and caspase3 expression, which inhibited immune cell apoptosis. The expression of vascular growth factor VEGF was significantly upregulated, that is beneficial to alleviate symptoms of spleen deficiency. In addition, toxicological experiments showed that BYD was safe for the internal organs and blood system of mice. CONCLUSIONS:This study validated the efficacy and safety of BYD formula granules in the treatment of spleen deficiency, and preliminarily investigated the mechanism of BYD in improving spleen deficiency by inhibiting apoptosis and promoting angiogenesis. That provide reference for the further clinical application of BYD formula granules.

Acne vulgaris is a prevalent inflammatory skin disease affecting the folliculosebaceous unit. Current treatments, such as antibiotics and anti-inflammatory drugs, face challenges like drug resistance and side effects. Cryptotanshinone (CTS), a diterpenoid from Salvia miltiorrhiza, exhibits potential acne-treating effects by inhibiting sebaceous gland secretion, regulating perifollicular keratosis and exhibiting anti-inflammatory properties. However, its poor water solubility and skin permeability hinder clinical application. CTS was researched in the previous work and CTS cerasomes was prepared. However, the issues of low encapsulation rate and large particle size still existed. Here, we propose a strategy for encapsulating CTS using a glycyrrhizin-based carrier to address the issues above. Under microscopic observation, the glycyrrhizic acid-encapsulated CTS micelles (GA-CTS), with an average size of 24.81 ± 1.40 nm, exhibited a uniform spherical shape. In vitro permeation assay demonstrated that the water solubility and skin permeability of CTS were significantly improved, indicating a higher bioavailability. GA-CTS also inhibited Cutibacterium acnes (C. acnes) and reduced Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β) expression in HaCaT cells. In vivo, a BALB/c mouse acne model was established via intradermal C. acnes injection. HE staining, IL-1β immunohistochemistry, and qRT-PCR were used to assess the treatment effect of GA-CTS. Compared to CTS or GA alone, GA-CTS significantly inhibited C. acnes growth, reduced skin swelling, and improved skin histology. Notably, GA-CTS inhibited keratin 16 (K16) gene expression, improving abnormal skin keratinization, and regulated 5-α reductase mRNA expression, potentially impacting androgen metabolism and offering another mechanism for acne treatment. In conclusion, GA-CTS micelles show promising potential in acne treatment, offering new insights and methods for anti-acne drug development and clinical application.

Current acne therapies face major limitations, including antibiotic resistance and skin irritancy. In this study, a synergistic strategy combining cryptotanshinone and madecassoside was developed through functional complementarity. Antibacterial activity against Cutibacterium acnes was evaluated using minimum inhibitory concentration (MIC) and inhibition zone assays, while cytotoxicity was assessed using human keratinocytes (HaCaTs). Anti-inflammatory efficacy was quantified by measuring tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in lipopolysaccharide-stimulated macrophages and a copper sulfate (CuSO4)-induced zebrafish inflammatory model. Systemic safety was examined in zebrafish models (developmental toxicity and sodium dodecyl sulfate-induced irritation). Finally, macroscopic severity, histopathology, and serum cytokines were used to assess an oleic acid-induced rat acne model. Cryptotanshinone inhibited Cutibacterium acnes (minimum inhibitory concentration = 62.5 μg/mL) but exhibited cytotoxicity (>5 μg/mL) and irritancy (≥1000 μg/mL). Madecassoside eliminated cryptotanshinone-induced cytotoxicity and reduced irritation. Importantly, the combination maintained antibacterial efficacy while synergistically enhancing anti-inflammatory effects, achieving a 94% reduction in follicular hyperkeratosis compared with 39% for cryptotanshinone alone (p < 0.01), alongside normalization of histopathology and cytokine levels. In conclusion, madecassoside functionally complements cryptotanshinone by neutralizing its cytotoxicity and irritancy, enabling a safe, synergistic therapy that concurrently targets antibacterial and anti-inflammatory pathways in acne pathogenesis.

BACKGROUND:The subtribe Malaxidinae encompasses diverse species, many of which possess remarkable medicinal properties that have been employed in traditional Chinese medicine for centuries. Although recent advancements have improved our understanding of the backbone phylogeny of Malaxidinae, clarifying the complex intergeneric relationships remains challenging, largely owing to limited genomic data. To address this gap and further investigate the genetic diversity and evolutionary patterns within this subtribe, we sequenced and assembled complete chloroplast (cp.) genomes from sixteen Malaxidinae species. These newly acquired genomic resources, combined with two previously published cp. genomes from closely related species, were incorporated into a comprehensive comparative genomic and phylogenomic analysis. RESULTS:The complete cp. genomes of all 18 Malaxidinae species were analyzed, revealing lengths ranging from 143,062 bp to 158,785 bp. Each genome contains 123-133 genes, including 74-86 protein-coding genes, 38 tRNA genes, 8 rRNA genes and 1-8 pseudogenes. The chloroplast genomes of Malaxidinae species exhibit significant structural diversity, with particularly pronounced variations observed in the ndhF and ycf1 genes located at the IR/SSC boundary regions. In certain species, the SSC regions showed substantial size reduction, ranging from 10,224 to 15,582 bp. Notable variability in both gene loss and truncation patterns was observed in the ndh gene family across these species, accompanied by diverse modifications affecting the length, position, and pseudogenization of the ycf1 gene. Furthermore, our study identified genomic inversions and rearrangements occurring in both the LSC and SSC regions of specific species. The detection of abundant long dispersed repeats and SSRs provides valuable molecular markers for evaluating both intrageneric and interspecific polymorphism as well as genetic diversity patterns. Through codon usage bias analysis, we established that natural selection serves as the predominant evolutionary force shaping codon usage patterns in most Malaxidinae species. Detailed sequence alignment of the chloroplast genome revealed that structural variants are primarily concentrated within single-copy regions. Ten highly variable cpDNA markers were chosen as mutational hotspots, with the potential for development as DNA barcodes for Malaxidinae species. Our phylogenomic analysis clearly resolved the Malaxidinae into three well-supported major clades. Clade I comprises species of Liparis s.s., Malaxis, and Oberonioides. Clade II includes species of Crepidium, Dienia, Diteilis and Empusa. Clade III consists of species from the genera Blepharoglossum, Cestichis, Oberonia, Platystyliparis and Stichorkis. CONCLUSION:This research provides valuable insights into the unique characteristics of the chloroplast genome in Malaxidinae orchids, significantly advancing our comprehension of their evolutionary mechanisms and phylogenetic architecture. The acquired genomic data establish a crucial foundation to advance medical resources and aid in species differentiation.

BACKGROUND:Colorectal cancer (CRC) is a prevalent malignant tumor. As per the principles of Traditional Chinese Medicine (TCM), the primary pathogenesis of CRC is associated with a deficiency in vital energy. Licorice, known for its spleen-tonifying and qi-enhancing efficacy, shows potential for preventing and treating CRC. Nevertheless, the pharmacological foundation and underlying mechanisms of licorice in CRC treatment are still not fully understood. METHODS:UPLC-Q-Exactive Orbitrap MS was employed to analyze the components of Licorice extracts (LEs) and the substances absorbed into the bloodstream. The key active substances and potential mechanisms were screened using network pharmacology and docking techniques. The selected results were validated in vivo and in vitro. RESULTS:43 compounds of LEs were absorbed. LEs demonstrated inhibitory effects on the development and progression of CRC in mice and cells. The study revealed that the absorbed components of LEs triggered tumor cell apoptosis, decreased the expression of EGFR and HIF-1α, and suppressed the activation of the RAS/RAF/MEK/ERK signaling pathway. CONCLUSION:LEs exert anti-CRC effects through apoptosis induction and RAS/RAF/MEK/ERK pathway inhibition. These findings demonstrate the great potential of TCM in the treatment of CRC and support its broader clinical application in combination chemotherapy and targeted therapy.

Traditional anti-inflammatory and antimicrobial drugs often fail to address all aspects of acne vulgaris and are prone to causing adverse effects such as skin irritation, dryness, and allergic reactions. Consequently, there is a growing preference for the exploration of natural and safer therapeutic agents from plant sources. In this study, we developed a coassembled CU-GA hydrogel formed by cross-linking small active molecules─glycyrrhizic acid (GA) and a cryptotanshinone-peptide conjugate (CTS-G-GLU, CU). The CU-GA hydrogel exhibits a distinct nanofibrous structure under a microscopic view. Material characterization and molecular dynamics simulations explain that its assembly mechanism may be related to a series of noncovalent interactions. Preliminary acne treatment tests show that the hydrogel has high skin permeability, biocompatibility, and effective antibacterial and anti-inflammatory properties. This efficient formulation, free of external gelling agents, is particularly suitable for sensitive, acne-prone skin and will revolutionize the development of emerging acne treatment hydrogels.

Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE-/- mice. Furthermore, biocompatibility was assessed through hemolysis, cytotoxicity assays, and in vivo safety studies, confirming its suitability as a safe therapeutic agent. In conclusion, this work not only identified four anti-AS polyphenols from traditional herbs but also established an MPN-based co-delivery system for synergistic anti-AS therapy, providing a comprehensive paradigm from drug discovery to formulation development.

Sigal peptides have garnered remarkable efficacy in rejuvenating photoaged skin and delaying senescence. Nevertheless, their low solubility and poor permeability bring about a formidable challenge in their transdermal delivery. To address this challenge, bioactive ionic liquids (ILs) synthesized from natural glycyrrhizic acid (GA) and oxymatrine (OMT) with eminent biocompatibility is first prepared. The components ratios and inherent forming mechanisms of GA-OMT (GAO) are optimized by molecular dynamics simulations and density functional theory calculations. Remarkably, GAO can significantly improve the sparingly soluble properties of palmitoyl pentapeptide-4 (PAL-4), a model peptide drug. Subsequently, GAO self-assembled micelles loading PAL-4 (GAO/PAL-4-SM) are fabricated without additional auxiliary materials. The permeation and subcutaneous retention of PAL-4 are significantly promoted with 10wt.% GAO-SM. Moreover, GAO ILs facilitated PAL-4 permeation by enhancing its miscibility and interaction with stratum corneum (SC), offering a pulling effect and micellar structures for PAL-4, as elucidated by computational simulations. In cellular and animal photoaging experiments, GAO/PAL-4-SM possessed remarkable capabilities in boosting collagen and hyaluronic acid regeneration, mitigating inflammation and apoptosis, accelerating macrophage M2 polarization, thereby lessening skin wrinkles and leveraging elasticity. Collectively, the research innovatively designed an ILs self-assembled nano-micellar transdermal delivery system to enhance the permeability and anti-photoaging effect of signal peptides.

Nanoparticulate drug delivery systems (NDDS) have revolutionized modern medicine by significantly improving drug targeting, bioavailability, and therapeutic efficacy. Despite the clinical success of over 90 approved nanomedicines, the development of NDDS remains challenging due to the complexity of formulation design, optimization, and characterization processes. Artificial intelligence, particularly machine learning (ML), offers powerful data analytics and predictive capabilities that can address these challenges. This review systematically summarizes recent advances in ML applications across various NDDS formulations, including polymeric nanoparticles, lipid nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, nanosuspensions, lipid-based hybrid NDDS, self-emulsifying drug delivery systems, niosomes, and nanocrystals. We also summarize how ML algorithms could help predict critical quality attributes of NDDS, such as particle size, shape, surface properties, drug encapsulation efficiency, drug loading efficiency, drug release behavior, and stability. Furthermore, we discuss existing challenges and prospects for the formulation development empowered by ML in NDDS. In conclusion, this review provides a comprehensive overview of the transformative potential of ML in improving the formulation development of nanomedicines, ultimately accelerating their clinical translation.

Obesity has become a major global health problem, and strategies to improve metabolic disorders are urgently needed. This review focused on the roles of natural active ingredients in regulating metabolic communication between the liver and brown adipose tissue (BAT), especially highlighting the associated signaling pathways and structure-activity relationship (SAR). Natural polyphenols, flavonoids, terpenoids, and their potential in modulating metabolism were elaborated. Particularly, some signaling factor pathways including insulin, adiponectin, leptin, NRG4, FGF21, inflammatory factor, and BMP were summarized, detailing how natural active ingredients modulated the liver-BAT metabolic crosstalk, such as celastrol, genistein, sesamin, etc. FGF21 and NRG4 acted as key signaling factors, playing important transduction roles in the metabolic crosstalk between the liver and BAT. More importantly, SAR of flavonoids, phenolic acids, polysaccharides, and terpenoid compounds was discussed. The presence of functional groups, hydroxyl or methoxyl substituents, and molecular size were analyzed in relation to the interaction between compounds and biological targets. Furthermore, how structural modifications enhanced bioactivity and bioavailability while reducing side effects was elucidated. In conclusion, natural active ingredients played an important role in modulating metabolic crosstalk between the liver and BAT, underscoring the potential of these components in treating metabolic disorders. Further research on SAR of different natural active ingredients and their long-term health impacts are still needed to provide more effective and safer natural solutions for metabolic diseases prevention and treatment.

ETHNOPHARMACOLOGICAL RELEVANCE:Rosa cymosa Tratt is a traditional Chinese medicine with long history of medicinal use. The fruit of R. cymosa, which named as 'Xiao Jin Ying Zi, has been documented has the function of treatment of contusions, injuries, and wind-phlegm cough. AIMS OF THE STUDY:The objective of this study was to isolate the biological polyphenolic extracts from R. cymosa fruit, identify its main components, and evaluate its antioxidant and anti-inflammatory effects in vitro. METHODS:The polyphenolic extract from R. cymosa fruit (PRCF) was obtained using an optimized orthogonal extraction method and purified by D140 macroporous resin column. The components were characterized by UV and IR spectroscopy. The composition of PRCF was analyzed using the UPLC-QTRAP-MS system. The antioxidant activities of PRCF were systematically evaluated through the inhibition rates of various radicals, iron ion reduction power, and total reducing power. Furthermore, the anti-inflammatory activity of PRCF was assessed using a lipopolysaccharide-stimulated macrophage model. The expression of anti-inflammatory cytokines was evaluated at both the transcriptional and translational levels. Additionally, protein expressions within the NF-κB and autophagy pathways were analyzed. Furthermore, the nuclear translocation of P65 protein and lysosomal levels in macrophages were assessed to elucidate the potential anti-inflammatory effects of PRCF. RESULTS:The PRCF primarily comprises phenolic acids and flavonoid components, including protocatechuic acid, gentisic acid, and procyanidin B2. UV and IR spectra indicated characteristic absorptions of aromatic rings, hydroxyl groups, and carboxyl groups. The PRCF showed excellent scavenging activity against ABTS and DPPH radicals, as well as significant total reducing power. Furthermore, PRCF inhibited the secretion of NO, TNFα and IL-6 in LPS-induced macrophages, mRNA and protein expression of iNOS and COX2, as well as the phosphorylation and nuclear translocation level of P65 proteins. Additionally, PRCF significantly decreased the expression of P62 proteins and increased conversion of LC3-I to LC3-II protein and the lysosomal expression in LPS-induced inflammatory macrophages. CONCLUSIONS:The purified polyphenolic-rich extract PRCF demonstrated strong antioxidant activity by scavenging multiple free radicals. Additionally, the extract suppressed inflammatory responses in activated macrophages by modulating autophagy levels and regulating protein expression in the NF-κB pathway.

Ethnopharmacological relevance: Blossom of Citrus aurantium L. var. amara Engl. (CAVA) has been popularly consumed as folk medicine and dietary supplement owing to its various beneficial effects and especially antiobesity potential. Our previous study predicted that eriodictyol was probably one of the key active compounds of the total flavonoids from blossom of CAVA. However, effects of eriodictyol in anti-obesity were still elusive. Aim of the study: This study was performed to explore the precise role of eriodictyol in white adipose tissue (WAT) browning and hepatic lipid metabolism, and simultaneously, to verify the impact of eriodictyol on the total flavonoids of CAVA in losing weight. Materials and methods: The pancreas lipase assay was conducted and oleic acid-induced HepG2 cells were established to preliminarily detect the lipid-lowering potential of eriodictyol. Then, high fat diet-induced obesity (DIO) mouse model was established for in vivo studies. The biochemical indicators of mice were tested by commercial kits. The histopathological changes of WAT and liver in mice were tested by H&E staining, Oil Red O staining and Sirius Red staining. Immunohistochemical, Western blot assay, as well as RT-qPCR analysis were further performed. Additionally, molecular docking assay was used to simulate the binding of eriodictyol with potential target proteins. Results: In vitro studies showed that eriodictyol intervention potently inhibited pancreatic lipase activity and reversed hepatic steatosis in oleic acid-induced HepG2 cells. Consistently, long-term medication of eriodictyol also effectively prevented obesity and improved lipid and glucose metabolism in diet-induced obesity mice. Obesity-induced histopathological changes in iWAT, eWAT and BAT, and abnormal expression levels of IL-10, IL6 and TNF-alpha in iWAT of DIO mice were also significantly reversed by eriodictyol treatment. Eriodictyol administration significantly and potently promoted browning of iWAT by increasing expression levels of thermogenic marker protein of UCP1, as well as brown adipocyte-specific genes of PGC-1 alpha, SIRT1 and AMPK alpha 1. Further assays revealed that eriodictyol enhanced mitochondrial function, as shown by an increase in compound IV activity and the expression of tricarboxylic acid cycle-related genes. Besides, eriodictyol addition markedly reversed hepatic damages and hepatic inflammation, and enhanced hepatic lipid metabolism in DIO mice, as evidenced by its regulation on p-ACC, CPT1-alpha, UCP1, PPAR alpha, PGC-1 alpha, SIRT1 and p-AMPK alpha expression. Molecular docking results further validated that AMPK/SIRT1 pathway was probably the underlying mechanisms by which eriodictyol acted. Conclusion: Eriodictyol exhibited significant anti-obesity effect, which was comparable to that of the total flavonoids from blossom of CAVA. These findings furnished theoretical basis for the application of eriodictyol in weight loss.

The escalating global obesity crisis and its associated metabolic disorders have posed a significant threat to public health, increasing the risk of major health issues such as cardiovascular diseases and type 2 diabetes. Central to metabolic regulation are the liver and brown adipose tissue (BAT), which orchestrate glycolipid metabolism, thermogenesis, and energy homeostasis. Emerging evidence highlights the role of natural bioactive compounds-such as polyphenols (e.g., resveratrol, curcumin), alkaloids (e.g., berberine), and terpenoids (e.g., paeoniflorin, shikonin)-in modulating liver-BAT crosstalk. These compounds influence critical pathways, including AMPK activation, PPAR signaling, and UCP1-mediated thermogenesis, to enhance lipid oxidation, suppress gluconeogenesis, and improve insulin sensitivity. This review systematically examines how these natural agents regulate metabolic interplay between the liver and BAT, addressing their effects on energy expenditure, carbohydrate utilization, and lipid mobilization. Key mechanisms involve the suppression of hepatic lipogenesis, promotion of BAT-mediated thermogenesis, and secretion of hepatokines (e.g., FGF21) and batokines that coordinate interorgan communication. By synthesizing preclinical and clinical findings, we highlight the translational potential of dietary interventions and nutraceuticals targeting liver-BAT axis dysfunction. Future research should prioritize mechanistic studies, dose optimization, and personalized approaches to harness these compounds for combating obesity-related diseases. These insights underscore the promise of natural bioactive molecules as adjuvants to lifestyle modifications, offering innovative strategies for metabolic health restoration.