Cytochrome P450 (CYP450) enzymes are the most important phase I drug-metabolizing enzymes in humans, and regulation of their activity is directly related to drug efficacy and safety. As herbal medicines gain worldwide popularity, their concurrent use with drugs has become more common. The effect of phytochemicals from herbal sources on CYP450 activity is a critical factor contributing to clinical drug interactions. When CYP450 activity is inhibited, it is easy to cause the accumulation of substrate drugs and cause toxic side effects, or the formation of toxic intermediates due to altered metabolic pathways, which seriously threaten the medication safety of patients. However, only a limited number of herbs have been evaluated for their impact on CYP450 enzyme activity, and data on the inhibitory effects of key CYP450 isoforms involved in drug metabolism remain scarce. Particularly noteworthy is the lack of research on the mechanisms of herb-drug interactions (HDIs) and the constituents of compound herbs, which impedes comprehensive identification and evaluation of potential clinical risks. This paper provides a systematic summary of CYP450 phytochemical inhibitors such as alkaloids, quinones, flavonoids, terpenoids, and coumarins in herbal medicine. In addition to the common CYP450 isoforms (e.g., CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), this review also focuses on some less frequently studied isoforms, including CYP1B1, CYP7A1, CYP8B1, CYP17A1, and CYP19A1. Through an in-depth analysis of the current research limitations, this study proposes targeted directions for technological innovation and research standardization, thereby providing a scientific basis for addressing the research gap in HDIs and herb-herb interactions (HHIs) and formulating strategies for the rational use of herbs and standards for safety evaluation.
Lung cancer remains an aggressive and highly prevalent disease worldwide, causing an estimated 1.8 million deaths in 2022 and becoming a leading cause of cancer-related mortality. Resistance to current therapies necessitates novel approaches that target the tumour immune microenvironment (TIME), which is crucial for disease progression. Studies suggest that certain phytochemicals can enhance antitumour immunity by modulating the TIME. This systematic review aimed to elucidate and synthesise the mechanisms by which phytochemicals exert antitumour immunomodulatory effects in lung cancer and to assess their therapeutic potential and translational challenges. We comprehensively reviewed the literature from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) until December 2025. Phytochemical mechanisms were analysed and classified based on their chemical structures and specific targets within the TIME. Phytochemicals effectively reprogrammed the immunosuppressive TIME using multi-target strategies. Key actions include the inhibition of immunosuppressive cells-such as myeloid-derived suppressor cells (MDSCs), Treg cells, and M2-polarised macrophages (e.g., via STAT3 downregulation by dihydroisotanshinone I)-activation of effector cells (e.g., NK cells, CD8+ T cells, and M1 macrophages), and the reversal of T helper cell drift (e.g., panaxan and aesculetin). This multipronged modulation offers superior efficacy by enhancing CD8+ T cell responses and overcoming functional exhaustion. This review validates the significant potential of phytochemicals as novel multi-target therapeutic agents for TIME-targeted therapy in lung cancer. Future research should prioritise addressing pharmacological challenges to accelerate rational clinical integration.
Atherosclerosis and its complications significantly affect human health globally. The etiology of atherosclerosis is multifaceted, with current research focusing on abnormalities in lipid metabolism, immune cell activation, inflammation, and epithelial damage. Currently, highly effective preventive and therapeutic strategies for atherosclerosis remain lacking. Recent reports have indicated the anti-atherosclerotic effects of medicinal herbs from the Araliaceae family, including Panax ginseng C. A. Mey., Panax notoginseng, Panax quinquefolius L., and Panax japonicus. The pharmacological effects of these herbs on atherosclerosis include lipid metabolism, immune cell activation, inflammation, oxidative stress, endothelial function, cell proliferation and migration, angiogenesis, apoptosis, autophagy, and gut microbiota homeostasis. This review aims to comprehensively elucidate, summarize, and update the protective effects and underlying mechanisms of Araliaceae herbs against atherosclerosis.
Affecting approximately 85% of expectant mothers during the first trimester, nausea and vomiting of pregnancy (NVP) are frequently reported symptoms. Despite numerous existing systematic reviews and meta-analyses (SRMs), findings remain inconsistent. Consequently, this study assesses the quality of these prior SRMs and investigates the efficacy of ginger as a treatment for NVP. A comprehensive search was conducted across PubMed, Scopus, Cochrane, and Web of Science from their inception through December 30, 2024. This review includes peer-reviewed English-language SRMs investigating ginger as a therapeutic intervention for pregnancy-related nausea and vomiting. Methodological rigor was evaluated using the AMSTAR-2 checklist, while evidence quality was assessed via the GRADE approach. Findings are synthesized narratively through content analysis. The study protocol was prospectively registered in the PROSPERO database. This study analyzed 18 systematic reviews, of which eight (44%) incorporated meta-analyses. The Rhodes Index of Nausea and Vomiting (RINV) emerged as the primary tool for evaluating outcomes. Regarding study reporting and transparency, seven studies registered their protocols in PROSPERO, while eight adhered to the PRISMA checklist. Overall, the included reviews demonstrated low methodological quality, with a mean score of 11.77. Specifically, 28% (n = 5) were rated as high quality, 28% (n = 5) as moderate, 22% (n = 4) as low, and 22% (n = 4) as critically low. Taking ginger supplements (usually between 450 and 1950 mg daily) significantly decreases the severity and occurrence of nausea and vomiting compared to a placebo. This benefit is more noticeable for nausea than for vomiting, where the results are less consistent. Numerous studies have shown that ginger does not raise the risk of adverse effects, such as spontaneous abortion or side effects like heartburn and drowsiness, when compared to a placebo or vitamin B6. Current evidence clearly shows that ginger is a safe and effective treatment for nausea and vomiting during pregnancy, with effectiveness similar to vitamin B6 and some traditional medications, and it has a good safety profile. Ginger can be recommended as a dependable medicinal herb for women dealing with NVP, though more research is needed to determine the best doses and confirm long-term safety.
Ganoderma lucidum, a revered medicinal mushroom with a rich history in traditional East Asian medicine, has garnered significant scientific attention for its diverse pharmacological properties. This comprehensive review synthesises recent advancements in understanding the phytochemistry, biological activities and therapeutic applications of G. lucidum . We delve into the intricate composition of its bioactive compounds, including polysaccharides, triterpenoids, sterols and phenolic compounds, elucidating their mechanisms of action in immunomodulation, anti-inflammatory responses, antioxidant defence, hepatoprotection and anticancer potential. Furthermore, this review examines emerging applications in nanotechnology, where G. lucidum extracts are utilised for the green synthesis of nanoparticles and as components in advanced drug delivery systems, antimicrobial nanomaterials and biosensors. We also discuss its expanding role in nutraceuticals, functional foods and cosmeceuticals, highlighting its anti-aging, skin-brightening and calming properties. Finally, the safety profile and toxicological evaluations of G. lucidum are critically assessed, alongside its growing economic significance. This review underscores the immense therapeutic potential of G. lucidum as a natural resource for modern medicine and biotechnology, while also identifying key challenges and future directions for research to facilitate its broader clinical and industrial translation.
The use of medicinal products derived from cannabis and its synthetic analogues has grown in recent years for various health conditions, which led to an increase in systematic reviews (SR) on the topic. The objective of this overview was to identify, synthesize, and critically appraise the evidence from SR on the benefits and harms of cannabis derivatives when used for therapeutic purposes in different health conditions. A comprehensive search was conducted to identify all relevant SR in Embase, Epistemonikos, MEDLINE, and Cochrane Database of Systematic Reviews. The inclusion criteria was SR assessing the effects of cannabis and its derivatives for any clinical condition that included only randomized controlled trials. A structured selection and extraction process was performed by two independent researchers. The methodological quality of the included SR was assessed using AMSTAR-2. This overview included 102 SR, 68.6% of which were of critically low quality and 17.6% were of high quality. There is low to moderate certainty of evidence of benefits from these interventions for ulcerative colitis, chronic non-cancer pain, Crohn's disease, multiple sclerosis, and post-chemotherapy nausea and vomiting. The results point to a lack of benefits for sleep disorders, chronic cancer pain refractory to opioids, pain related to radiotherapy, and pain in people receiving palliative care. For other conditions, the certainty of the evidence was very low or not assessed. This overview opens a broad and complex field for the development of primary studies to evaluate the effects of cannabinoids as primary or adjunctive therapy for different health conditions and reinforces the importance of safety assessment. Decision-makers and guideline developers can be guided by the results summarized in this overview. However, when making formal recommendations, it is essential to consider the quality of the SR and the certainty of the evidence identified for each outcome.
Liver diseases such as viral hepatitis, fatty liver disease, autoimmune and genetic disorders, drug-induced liver injury, hepatocellular carcinoma, and cirrhosis represent a major global health burden, while current pharmacotherapies remain limited by suboptimal efficacy, adverse effects, and poor accessibility. Ethnopharmacological use of medicinal plants offers a rich resource for discovering novel hepatoprotective agents, particularly secondary metabolites including alkaloids, flavonoids, terpenoids, glycosides, tannins, and saponins that target key pathogenic processes such as oxidative stress, inflammation, fibrosis, apoptosis, and metabolic dysregulation. This review systematically integrates traditional knowledge with modern evidence from in vitro, in vivo, preclinical, and clinical studies to highlight plant-derived phytoconstituents with demonstrated benefits across the spectrum of liver diseases, including clinically investigated agents such as silymarin, glycyrrhizin, curcumin, resveratrol, and ginsenosides. Mechanistic sections summarize disease progression from inflammation to fibrosis, cirrhosis, and hepatocellular carcinoma, and delineate how specific phytoconstituents modulate signaling pathways, redox homeostasis, lipid metabolism, and cell death programs, while pharmacokinetic data address absorption, distribution, metabolism, excretion, and strategies to overcome low oral bioavailability. The article also contrasts the limitations of current synthetic drugs with regulatory advances for botanical products across major agencies (FDA, EMA, WHO, and Asian regulators), and outlines methodological innovations including high-throughput screening, cheminformatics, in silico docking, organoid and liver-on-chip models, and nanotechnology-based delivery systems that can accelerate phytoconstituent-driven drug development. Overall, this review provides a comprehensive framework that links ethnomedicinal use, experimental validation, regulatory context, and technological progress, and identifies priority phytoconstituents and research directions for translating plant-based hepatoprotective agents into standardized, clinically effective therapies for liver disease.
Cancer remains a leading cause of global mortality, with tumor heterogeneity, recurrence, metastasis, and drug resistance posing significant challenges to conventional therapies, which are often limited by toxicity and efficacy. Epigenetic regulation, particularly histone modifications such as methylation, acetylation, phosphorylation, and lactylation, plays a pivotal role in orchestrating gene expression and tumor progression, representing promising yet complex therapeutic targets. Bioactive compounds derived from natural plants, characterized by multi-target activity and low toxicity, have emerged as potent modulators of histone modifications, capable of influencing tumor growth, metastasis, and the tumor microenvironment. Here, we provide a comprehensive review of recent advances elucidating how natural products influence cancer progression and reshape the tumor immune microenvironment by regulating histone modifications. We integrate current knowledge of key histone marks, modifying enzymes, and signaling pathways, proposing a unified framework linking natural compounds, epigenetic regulation, and tumorigenesis. By uncovering these molecular mechanisms, we highlight that plant bioactive compounds can reshape the tumor immune microenvironment through histone modifications to inspire the development of novel, safer, and more effective anticancer agents.
Radioresistance remains a key barrier in breast cancer (BC) treatment. Baicalein, a flavonoid from Scutellaria baicalensis, has shown potential to enhance radiosensitivity. This study investigates its efficacy and mechanism in radioresistant BC models. Radioresistant BC cell models were established via fractionated irradiation and validated by clonogenic assays. Baicalein's radiosensitizing effects were assessed using clonogenic survival and DNA damage assays (γ-H2AX foci and neutral comet). KEGG and protein-protein interaction analyses identified Rac1 as a key mediator. Molecular docking and 100 ns molecular dynamics (MD) simulations evaluated the binding stability of the Rac1-baicalein complex, with binding free energy calculated via gmx_MMPBSA. Rac1 activity, immunoblotting, immunofluorescence, and comet assays demonstrated that baicalein inhibits Rac1 activity and delays DNA repair. In vivo xenograft studies (n = 5 mice/group) with immunohistochemistry validated Rac1 pathway inhibition. Baicalein enhanced radiosensitivity in BT549 (radiation enhancement ratio, ER = 2.20 ± 0.12) and MCF7-R cells (ER = 1.38 ± 0.10). Molecular docking revealed a strong binding affinity (-6.87 kcal/mol) between baicalein and Rac1, with MD simulations indicating a relatively stable interaction (binding free energy: -73.42 kJ/mol). Surface plasmon resonance (SPR) analysis revealed a direct interaction between baicalein and Rac1 protein with moderate affinity (KD = 2.91 × 10-6 M). High Rac1 expression correlated with poorer clinical outcomes in overall survival (OS), disease specific survival (DSS), and progress free interval (PFI). Baicalein delayed DNA repair after radiation by inhibiting Rac1 activity via the NHEJ pathway, an effect reversed by a constitutively active Rac1-Q61L plasmid. In vivo, baicalein inhibited Rac1, slowing tumor growth and enhancing radiosensitivity. Baicalein is a potential radiosensitizer, offering a novel strategy to overcome radioresistance in breast cancer therapy.
The gut-lung axis constitutes a dynamic, multidirectional communication platform between the gastrointestinal and respiratory tracts. Its complexity arises from the integrated crosstalk among the microbiota, immune system, and redox homeostasis, collectively influencing disease susceptibility and progression. The gut microbiota directly impacts pulmonary inflammation through immune modulation and oxidative stress regulation. Conversely, disturbances in lung homeostasis, including shifts in the local microbiota, can in turn reshape gut microbial communities, establishing a bidirectional feedback loop. Polyphenols, a class of bioactive compounds abundant in plant-based foods, have emerged as key modulators of this bidirectional network. The primary objective of this review is to systematically synthesize current knowledge on the mechanisms by which polyphenols orchestrate gut-lung axis. We critically examine how they modulate gut and lung microbiota, redox homeostasis, and immune responses, thereby impacting the progression of respiratory and gastrointestinal diseases. This review aims to highlights the translational significance of polyphenols as dietary components and therapeutic candidates, while identifying key knowledge gaps, such as dose optimization and combination strategies, to guide future research aimed at harnessing the gut-lung axis for disease prevention and treatment.
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with limited effectiveness and safety of current drug therapies. Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid present in traditional Chinese medicines used clinically as retention enemas for UC, but its direct effects and mechanisms remain unclear. This study evaluated the therapeutic impact of BA enema in dextran sulfate sodium (DSS)-induced colitis by monitoring disease activity index (DAI), colon length, and histopathology, and by assessing inflammatory cytokines, mucosal tight junction, and mucin-2 (MUC2) expression. Colonic mucosa-associated microbiota were profiled by 16S rRNA gene sequencing. Potential BA targets were predicted using Swiss Target Prediction and validated by molecular docking, molecular dynamics simulations, cellular thermal shift assay, and biolayer interferometry. The functional relevance of the vitamin D receptor (VDR) was examined using a VDR antagonist in vivo and in vitro, and transcriptomic datasets from UC patients were analyzed to define VDR expression patterns. BA enema markedly attenuated DSS-induced colitis, such as reducing the DAI, inhibiting colonic damage, and improving colon length shortening. The BA also significantly restored the tight junction proteins, associated mucin proteins, and mucin-2 (MUC2). The BA reduced potentially pathogenic bacteria in the colonic mucosa. In addition, BA significantly restored the VDR proteins, and the VDR antagonist weakened the effects of BA in vivo and in vitro. The binding site between VDR and BA was Trp286. Transcriptomic analyses confirmed VDR downregulation in UC. These findings indicate that BA enema alleviates experimental colitis in part by targeting VDR to protect the intestinal mucosal barrier and modulate mucosa-associated microbiota, supporting BA as a promising candidate for UC treatment.
Acute liver injury (ALI) is a severe public health problem closely associated with oxidative stress, inflammation, and hepatocyte injury, leading to high mortality. Fucoxanthin (Fx), a marine carotenoid found in brown seaweeds, has various beneficial effects against multiple diseases. However, the potential role of Fx on ALI remains unclear. This study aims to explore the pharmacological potential of Fx in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced ALI. The therapeutic effect of Fx on ALI was primarily evaluated using a mouse model induced by LPS/D-Gal, focusing on pathological changes, oxidative stress, inflammation, and pyroptosis. Additionally, the effects of Fx on cell pyroptosis and its molecular mechanisms were explored in an in vitro pyroptosis model established by inducing macrophages with LPS/Nigericin. Fx significantly alleviated the LPS/D-Gal-induced histopathological progression and hepatocyte apoptosis, reducing plasma levels of ALT, AST, and LDH. It also obviously decreased hepatic MDA levels while increasing antioxidant enzyme activities and GSH concentration compared to LPS/D-Gal-treated mice. These antioxidant effects were linked to the upregulation of hepatic Nrf-2, HO-1, and GCLC expression. Furthermore, Fx treatment alleviated macrophage accumulation and downregulated the expression of pro-inflammatory factors in the liver. Importantly, Fx administration suppressed NLRP3 inflammasome-dependent canonical pyroptosis both in LPS/D-Gal-treated mice and LPS/Nigericin-stimulated macrophages, potentially mediated by the suppression of MAPKs and NF-κB pathways. These findings suggest that Fx could be an effective strategy to prevent ALI, particularly in cases associated with NLRP3 inflammasome-mediated pyroptosis.
Diabetic nephropathy (DN) is a major complication of diabetes. Swietenine (Swi), a natural compound derived from the fruit of Swietenia macrophylla , has shown beneficial effects in alleviating diabetic complications. However, its underlying mechanism for treating DN remains unclear. This study aimed to elucidate the therapeutic effects and molecular mechanisms of Swi against DN through in vitro and in vivo experiments. A model of streptozotocin/high-fat diet (STZ/HFD)-induced Sprague-Dawley (SD) rats was employed to evaluate the effects of Swi on improving DN renal fibrosis and enhancing autophagy in vivo. Followed based on the results of proteomics, network pharmacology, and molecular docking, the potential mechanism of Swi in treating DN was predicted, and subsequently the cell model of high glucose induced human renal tubular epithelial cells (HK-2) was established in vitro, and the potential mechanism of Swi's therapeutic effect was further validated through Western blot analysis, immunofluorescence, immunohistochemistry, and flow cytometry. After Swi treatment, levels of urinary protein, uric acid, creatinine, and urea nitrogen were significantly reduced in DN rats. Pathological improvements included decreased thickness of the tubular basement membrane, reduced PAS-positive deposits, less glycogen accumulation, and alleviated fibrosis. The number of autolysosomes increased significantly, especially with high-dose Swi. Immunofluorescence of renal tissue showed enhanced LC3B fluorescence intensity, suggesting restored autophagy levels. Western blot analysis revealed upregulation of LC3B and Beclin-1 and downregulation of p62 after Swi treatment. Immunohistochemistry indicated reduced expression of fibronectin (Fn) and collagen I (COI-I), indicating decreased extracellular matrix accumulation and renal injury. In high glucose-induced human renal tubular epithelial cells (HK-2), similar trends were observed. Swi treatment upregulated p-AMPK and p-ULK1 expression and downregulated p-mTOR. Overall, Swi significantly improved renal function and pathological damage in DN rats by activating the AMPK/mTOR/ULK1 signaling pathway, enhancing autophagy, reducing ROS production, and ameliorating mitochondrial injury, thereby delaying renal fibrosis progression. In conclusion, Swi exerts protective effects against DN by promoting autophagy and mitigating oxidative stress, suggesting its potential as a therapeutic agent for DN.
Pomegranate is an exceptional fruit that can have several beneficial effects on human health. The peel of pomegranate, a waste product, should be recovered as it still contains valuable constituents, including phenolic compounds, minerals and fibre. The recovery of bioactive compounds occurs through eco-sustainable extraction techniques that reduce costs and promote environmental sustainability and public health. Neurodegeneration is a pathological process causing progressive neuronal damage, potentially leading to cell death. Currently, no drug is known to cure neurodegenerative diseases definitively. A balanced diet rich in fruits and vegetables is associated with a lower risk of certain neurodegenerative conditions. The phytochemicals of plants and their beneficial bioactive compounds demonstrate promising therapeutic potential for human neurological diseases, exhibiting antioxidant and anti-inflammatory properties in the brain. This review aims to highlight the currently existing knowledge on the effects of pomegranate peel against neurodegenerative diseases and their mechanisms of action. The manuscript is intended for those who explore strategies for recovering waste materials and for those who investigate the effects of natural products on neurodegeneration. Prospects could include clinical trials in which pomegranate peel is used in the management of human neurodegenerative diseases.
Ginseng (Panax ginseng Meyer), one of the most widely known Chinese herbs, has been used in traditional medicine for centuries. Ginsenoside Rg5 (Rg5) can exert protective effects on the liver and activate the Nrf2 pathway. This study aims to investigate the mechanism of Rg5 alleviating acute liver injury (ALI), and the related mechanisms will be discussed. In vitro experiments, an ALI model was established using HepG2 cells. The DCFHDA, the JC-1, and the ferrous ion fluorescent probe detected the reactive oxygen species (ROS) level, the mitochondrial membrane potential change, and the iron ions level. The oxidative stress indexes were detected by biochemical analysis. Western blot was used to detect the m6A demethylation, Nrf2, and ferroptosis signaling pathways. For in vivo experiments, C57BL/6J mice were administered ethanol by gavage to establish the ALI model. In vitro, we observed that m6A methylation and FTO downregulation were involved in the ferroptosis process. Rg5 treatment alleviated ferroptosis after ethanol exposure, which was reflected by the decrease of intracellular iron content and ferroptosis-related proteins. The FTO knockdown exhibited ferroptosis-related proteins and YTHDF2 increase. The regulatory effect of FTO on ferroptosis was inhibited when Nrf2 was inhibited or knocked down. In vivo, HE staining revealed liver injury in the model group, with elevated liver-to-body weight ratios and serum ALT and AST levels. The Rg5 treatment has improved these phenomena. FTO, Nrf2, and anti-ferroptosis proteins were downregulated in the ethanol group, while the ferroptosis marker ACSL4 was upregulated. This study demonstrates that Rg5 alleviates ethanol-induced ALI by inhibiting ferroptosis via the FTO/YTHDF2/Nrf2 axis. Our work not only establishes a link between FTO-mediated m6A demethylation and ferroptosis but also provides new mechanistic insights into the hepatoprotective action of ginsenosides.
Laminin promotes tumor progression, but its role in small-cell lung cancer (SCLC) remains unclear. Curcumol, a natural compound from Curcumae Rhizoma, has anti-tumor activity. Here, we tested the hypothesis that Curcumol disrupts Laminin-Integrin β1 interaction to suppress SCLC. SBC-2 and H69 cells were cultured on Laminin-coated substrates. Cell functions were assessed by Transwell migration, colony formation, and MTT assays. Molecular mechanisms were investigated through qRT-PCR, Western blot, molecular docking, Co-IP, and Dot blot assays. Target specificity was confirmed by Integrin β1 mutagenesis. The therapeutic efficacy of Curcumol was evaluated in xenograft mouse models. Laminin enhanced malignant phenotypes in SCLC cells, accompanied by the activation of FAK/ERK and TGF-β/Smad2/3 pathways. Curcumol inhibited the laminin-promoted malignant phenotypes and epithelial-mesenchymal transition (EMT) in SCLC cells and suppressed the expression of related proteins. Mechanistic studies revealed that Curcumol directly bound to Integrin β1, competitively inhibiting the binding of Laminin to Integrin β1 and the activation of downstream signaling. Target specificity was validated through mutagenesis studies, where Curcumol exhibited reduced efficacy in Integrin β1-mutant cells. In vivo, Curcumol (100 mg/kg, oral) attenuated Laminin-driven tumor growth, suppressed EMT and FAK/ERK signaling, with no detectable toxicity. Integrin β1 is a key mediator of Laminin's pro-tumorigenic effects in SCLC. Curcumol disrupts Laminin-Integrin β1 interaction, inhibits FAK/ERK signaling and EMT, and suppresses tumor progression, representing a promising therapeutic strategy.
Cucurbitacin B is a naturally occurring tetracyclic triterpenoid extracted from plants in the Cucumis melo L. It demonstrates various pharmacological activities, such as hepatoprotective, anti-inflammatory, and anti-tumor effects. However, its therapeutic effect on inflammation-associated colorectal cancer (CRC) and its mechanism of action have not been elucidated. This study is aimed to investigate the effects of cucurbitacin B on inflammation-associated CRC and the mechanism of action. In vitro, the effect of cucurbitacin B on the inflammatory response and the related ZNF70/NLRP3 pathway was examined using western blotting, CCK-8, ELISA, and immunofluorescence assays. In the HCT116/THP-1 supernatant co-culture system, EdU, colony formation, and wound healing assays were performed to evaluate the effects of cucurbitacin B on the proliferation, migration, and epithelial-mesenchymal transition (EMT) progression of HCT116 cells in response to inflammation. In vivo, a mouse model of inflammatory CRC was constructed by administering azoxymethane (AOM) and dextran sodium sulfate (DSS). To study the role of ZNF70, an adenoviral vector AAV was used to knock out ZNF70 in mice. High-performance liquid chromatography (HPLC) was utilized to assess the toxic impact of cucurbitacin B on mice. Our results indicate that cucurbitacin B reduces the expression of NLRP3 inflammasome-associated proteins by downregulating the production of ZNF70. The co-culture experiment showed that cucurbitacin B inhibited the proliferation, migration, and EMT of HCT116 cells in the inflammatory microenvironment. In vivo studies demonstrated that the knockdown of ZNF70 restored body weight, improved colon length, reduced tumor burden, and increased survival rate in AOM/DSS model mice. This effect was further enhanced by the addition of cucurbitacin B. The HPLC results showed that cucurbitacin B was non-toxic to the heart, liver, spleen, lungs, and kidneys of mice. In conclusion, the downregulation of ZNF70 by cucurbitacin B inhibits the activation of NLRP3 inflammasomes and reduces the promoting effect of the inflammatory microenvironment on CRC proliferation, migration, and the EMT process. Our findings may provide new insights for the development of treatments for inflammation-associated CRC.
Atractylodes macrocephala Koidz. has long been used for invigorating Qi and traditionally prescribed for cancer treatment by Chinese medicine practitioners. Atractylenolide I (ATI) is a major active component in A. macrocephala and has inhibitory effects on various malignancies. Triple-negative breast cancer (TNBC)-related deaths are predominantly attributed to metastasis. However, the activity and mechanism of ATI on TNBC metastasis are unclear. Cell viability was detected by CCK-8 assay. Cell migration was determined by wound healing and transwell assays. The in vivo experiment was performed in 4 T1 spontaneous metastasis breast cancer nude mice. The mechanism was investigated by RNA-seq analysis, and further verified by bioinformatics, qPCR, western blot, and siRNA transfection analysis. ATI inhibited the growth of 4TI cells. Additionally, ATI repressed the wound healing, invasion, and migration activities of 4TI and MDA-MB-231 cells at a lower concentration. In vivo experiment revealed that while ATI (50 mg/kg) did not significantly inhibit tumor growth but markedly suppressed lung metastasis progression in a 4 T1 spontaneous metastasis mouse model. RNA-seq analysis of lung tissues showed that the extracellular matrix (ECM) signaling pathway was significantly suppressed by ATI. In addition, ATI inhibited the mRNA and protein levels of ECM-related members (SPP1, MMP9, and COL1A1) in vitro and in vivo. Bioinformatics analysis revealed that the overexpression of SPP1 correlated with the poor prognosis of breast cancer patients. Furthermore, ATI inhibited ECM activator pyrintegrin-induced wound healing. siRNA knockdown of SPP1 abolished ATI's inhibition on wound healing, cell migration, and expression of ECM-related genes/proteins in 4 T1 cells. Molecular docking showed that ATI interacted with Trp-106, Pro-44, and Leu-46 residues in SPP1 (-7.73 kcal/mol). Our findings suggest that ATI could suppress the lung metastasis of TNBC by inhibiting the SPP1-mediated ECM signaling pathway.
Idiopathic pulmonary fibrosis is a chronic, progressive disease in older adults with unclear pathogenesis and a lack of effective drugs. Columbianadin, a natural coumarin analog isolated from Angelicae pubescentis Radix, has a wide range of pharmacological effects; however, its effects on pulmonary fibrosis are unknown. This study investigates the anti-pulmonary fibrosis effects of columbianadin and their underlying mechanisms of action. An in vivo model of mouse lung fibrosis was established, and mice were randomly assigned to different doses of columbianadin. The effects of 5'-adenosine monophosphate-activated protein kinase (AMPK) on the anti-pulmonary fibrosis and anti-cellular senescence effects of columbianadin was observed by combining AMPK inhibitor and columbianadin. Cellular senescence was induced in vitro by hydrogen peroxide and treated with different concentrations of columbianadin, and we observed the effect of AMPK on the anti-cellular senescence effect of columbianadin by specifically silencing the AMPK gene. Columbianadin reduced the expression levels of collagen type I alpha 1 (col1-a1), alpha-smooth muscle actin (a-SMA), p21, and p16 in lung tissues of mice with pulmonary fibrosis, and these effects were inhibited by AMPK inhibitors. Similarly, Columbianadin reduced the expression levels of p21 and p16 in senescent cells. In addition, we found that columbianadin promoted Sirt1 and Sirt3 expression as well as AMPK phosphorylation, whereas the anti-cellular senescence effect of columbianadin and the effect of promoting the expression of Sirt1 and Sirt3 were suppressed by specific silencing of the AMPK gene. Columbianadin exerts its anti-pulmonary fibrosis effect by inhibiting cellular senescence via the AMPK-Sirt1/3 pathway. The present study provided new insight into a novel treatment of pulmonary fibrosis.
Lipid metabolic imbalance is a major contributor to metabolic disorders in humans and livestock, creating an urgent need for safe and effective regulatory approaches. Plant-derived compounds, characterized by favorable bioavailability and low toxicity, serve as promising candidates that regulate host lipid metabolism through dynamic crosstalk with the gut microbiota. This review systematically investigates the bidirectional crosstalk between plant bioactive compounds (e.g., polysaccharides, flavonoids, saponins and polyphenols) and the gut microbiota. We detail how gut microbes metabolize these compounds to enhance their bioactivity and bioavailability, while plant extracts reshape microbial community structure to enrich beneficial taxa. Furthermore, we elucidate the mechanisms underlying lipid metabolism regulation, focusing on three critical signaling pathways: (1) SCFAs-GPR43/41 signaling, (2) TLR4/NF-κB inflammation suppression, and (3) bile acid-FXR axis modulation. Collectively, this review synthesizes emerging evidence on plant-microbiota interactions as a novel therapeutic strategy to restore lipid homeostasis in animal models, offering foundational insights for agricultural and biomedical applications.