Aug 2026· Journal of Ethnopharmacology· Vol 373, pp.
122312
· 0 citations· 48 references
Medicine
TL;DR
Findings suggest that APS, the key active fraction of AM against IGT, mitigate IGT by modulating microbiota-metabolite-MAPK axis, offering novel mechanistic insight for the ethnopharmacological use of AM to mitigate chemotherapy-induced intestinal toxicity.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE
Astragalus membranaceus var. mongholicus (Bunge) P.K.Hsiao (AM), a classic Qi-tonifying herb, has been widely used for treating a range of inflammatory diseases. Nevertheless, the protective effects of AM against irinotecan-induced gut toxicity (IGT) remains insufficiently characterized, while the active pharmacological fractions and the underlying anti-IGT mechanisms have not been fully elucidated.
Aims
This study aimed to investigate the ameliorative effects of the water extract of AM and its fractions on IGT in mice, as well as to identify the most potent anti-IGT fraction and to reveal the underlying anti-IGT mechanisms.
Methods
The water extract of AM (WEA) was administered to an IGT murine model. Therapeutic efficacy was assessed using the Disease Activity Index (DAI), while histopathology was evaluated via H&E and PAS staining. Intestinal barrier integrity was examined by measuring ZO-1, Occludin, and Muc2 expression using RT-qPCR, immunofluorescence, and immunohistochemistry. Colonic pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were quantified by ELISA. Following confirmation of efficacy, four fractions were isolated and compared. The most effective fraction, Astragalus membranaceus polysaccharides (APS), was further investigated using 16S rRNA sequencing, microbial metabolomics, transcriptomic, and Western blot.
Results
APS significantly improved body weight loss and reduced DAI in IGT mice. H&E staining showed that APS ameliorated structural damage and inflammatory infiltration in colonic tissues. PAS staining revealed a notable increase in goblet cell numbers following APS treatment. RT-PCR and immunohistochemical staining confirmed that APS enhanced the expression of intestinal barrier markers (ZO-1, Occludin, Muc2) and promoted crypt proliferation (Ki67) in colonic tissue. Consequently, APS markedly reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in colonic tissues from IGT mice. 16S rRNA sequencing showed that APS regulated gut microbiota composition, thereby increasing the beneficial metabolites (e.g. butyrate acid) in colonic lumen. It was also found that APS significantly reduced the abundance of gmβ-GUS-producing bacteria, which in turn, decreasing gmβ-GUS enzymatic activity and the intestinal exposure levels of the toxic metabolite SN-38. Finally, transcriptomic analysis of colonic tissues revealed that APS suppressed the MAPK signaling pathway (MEK, ERK, P38, JNK) and down-regulated apoptosis-related genes (Bax, Bcl-2) in IGT mice.
Conclusion
Our findings suggest that APS, the key active fraction of AM against IGT, mitigate IGT by modulating microbiota-metabolite-MAPK axis, offering novel mechanistic insight for the ethnopharmacological use of AM to mitigate chemotherapy-induced intestinal toxicity.
The preliminary biological assessment suggests that the polysaccharide subfraction SM05 alleviated the symptoms of UC induced by DSS, and may be related to the activation of the Nrf2/Keap1 pathway, the inhibition of pyroptosis, and the regulation of the intestinal microbiota.
Qing Luo, Yangyang Xu, Zhihua Li et al.· Frontiers in Pharmacology· 0 citations
Background: Dangguibuxue decoction (DD), containing Angelica sinensis (Oliv.) Diels (AS) and Astragalus membranaceus (Fisch.) Bge. (AM) (1:5), is a well-known traditional Chinese medicine (TCM) used for strengthening qi and nourishing the blood. DD has shown therapeutic effects in nephropathy patients. However, the underlying mechanisms based on the traditional efficacy are still not fully elucidated. Methods: The chemical constituents in DD were identified using UPLC-MS/MS. Network pharmacology analysis was applied to predict the potential target genes and associated signaling pathways. A renal fibrosis mouse model was induced by the intraperitoneal injection of aristolochic acid I (AA I) at 3.0 mg/kg. Mice were treated with AM, AS, and DD at two dosages by oral gavage for 30 days. Body weights, serum biochemistry, hematology, and histopathology observations were assessed. The key targets predicted were validated using qRT-PCR and Western blotting. The active constituents were screened by molecular docking, and their anti-fibrotic effects were evaluated through in vitro assays. Results: DD effectively improved renal functions and alleviated AA I-induced renal fibrosis. DD alleviated anemia and upregulated the expression of Erythropoietin (EPO). Network pharmacology analysis indicated the involvement of signaling pathways, including the PI3K/Akt, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β (TGF-β) signaling pathways. Experimental validation further demonstrated that DD reduced the protein expression of HIF-1α, collagen I, and TGF-β, and the ratios of phosphorylated Smad2/3 to total Smad2/3. Molecular docking and in vitro assays suggested that rutin may be a potential bioactive compound in DD. Conclusions: This research indicated that DD ameliorated AA I-induced renal fibrosis in mice, which may be associated with the modulation of HIF-1α and TGF-β/Smad signaling pathways. Rutin may be a potential bioactive compound in DD with anti-fibrotic activity, but further studies are still needed to clarify the content of rutin in DD, the amount of its exposure in the body, and its contribution to the effects of DD.
BACKGROUND
Tsaoko Fructus, a traditional Chinese medicinal herb, has long been used to alleviate gastritis and enteritis. Nevertheless, the active constituents and underlying anti-inflammatory mechanisms remain insufficiently characterized.
PURPOSE
This study aims to optimize a polyphenol-rich fraction (3CB) from Tsaoko Fructus, evaluate its effects against ulcerative colitis (UC), and reveal the underlying mechanisms of action.
METHODS
The preparation of 3CB was optimized using response surface methodology (RSM), and its major constituents were identified by LC-PDA-MS analysis. A murine UC model was established by administering dextran sulfate sodium (DSS). To evaluate the effects of 3CB on UC mice, metagenomic sequencing of the intestinal microbiome and RNA sequencing of colon tissues were conducted. The anti-inflammatory activity of 3CB and its principal constituents was further verified by quantitative real-time PCR (qPCR), Enzyme linked immunosorbent assay (ELISA), Western blotting, immunohistochemical staining, and histopathological analysis. Network pharmacology, molecular docking, and surface plasmon resonance (SPR) assays were employed to elucidate the molecular mechanisms underlying the anti-inflammatory effects of 3CB.
RESULTS
3CB significantly alleviated UC symptoms in DSS-induced mice, reshaped the gut microbiota with reducing pathogenic Pseudomonadota and Deferribacterota while enriching beneficial Bacteroidota, and restored microbial amino sugar and nucleotide sugar metabolism pathways of intestinal flora. Additionally, 3CB preserved colonic oxidative phosphorylation, protected the mucus barrier, and suppressed inflammatory cell infiltration and the expression of cytokines. Seven major polyphenols were identified in 3CB, with epicatechin (3) and epiafzelechin (6) being the most abundant. Mechanistic investigation revealed that the anti-inflammatory effect of 3CB was partially dependent on the JNK1-modulated MAPK signaling pathway. JNK1 was identified as a direct target of 3CB, with epiafzelechin (6) exhibiting a high binding affinity (Kd = 10.4 μM).
CONCLUSION
3CB ameliorates UC potentially through modulation of gut microbiota, protection of the mucus barrier, and JNK1-targeted anti-inflammatory effects, highlighting its potential as a protective intervention for inflammatory bowel disease (IBD).
Pianchou Gongpan, Jing-yi Yang, Hang Fu et al.· Phytomedicine· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health challenge, necessitating the discovery of safe and effective therapeutic agents from natural dietary sources. Zanthoxylum bungeanum Maxim. (huajiao), a widely consumed pharma-food, contains abundant alkaloids with reported lipid-regulating, antioxidant, and anti-inflammatory activities, but its underlying mechanisms against MASLD remain unclear. This study aimed to evaluate the hepatoprotective effects of alkaloids from Z. bungeanum (ZBA) and elucidate its molecular targets using an integrated approach combining network pharmacology, transcriptomics, and experimental validation. To this end, FFAs-stimulated HepG2 cells and HFD-fed mice were employed to assess the effects of ZBA. The results showed that ZBA significantly alleviated hepatic lipid accumulation, improved insulin sensitivity, and reduced systemic inflammation. Mechanistically, omics analysis and molecular docking predicted the endocannabinoid system as a key target, and the cellular thermal shift assay confirmed that ZBA directly binds to both CB1 and CB2 receptors. Furthermore, pharmacological interventions using specific agonists and antagonists revealed that ZBA exerts a dual modulatory effect on the endocannabinoid system by suppressing CB1 overexpression and enhancing CB2 activity. This modulation subsequently activates the Akt/GSK3β/Nrf2 signaling cascade to restore lipid metabolism homeostasis and mitigate lipotoxicity in a dose-responsive regulatory trend. In conclusion, the present findings highlight that ZBA ameliorates MASLD by rebalancing the expression of CB1 and CB2 receptors, thereby modulating Akt/GSK3β/Nrf2 axis, thus providing a scientific basis for the development of ZBA as a functional food ingredient for metabolic health.
Wenyi Liang, Hengmin Yang, Yaqian Duan et al.· Food Science and Human Welln...· 0 citations
ETHNOPHARMACOLOGICAL RELEVANCE
Fengshi Gutong Capsules (FSGT) is widely used for the treatment of rheumatoid arthritis (RA). However, its clinical application is limited because it contains Aconiti Radix Cocta and Aconiti Kusnezoffii Radix Cocta (AA), and the mechanism of compatibility and detoxification remains unclear.
AIM OF THE STUDY
This study was to provide pharmacokinetic and mechanistic insights into the attenuation of AA-induced nephrotoxicity by FSGT compatibility.
MATERIALS AND METHODS
Collagen-induced arthritis (CIA) rats were treated with FSGT, its modified formulations (AA or FSGT-AA), or methotrexate, and renal injury was evaluated via biochemical indicators (BUN, CRE, UA) and histopathology. Aconite alkaloids (AC, HA, MA, BAC, BHA, BMA) were quantified in plasma, kidney, and urine by UPLC-MS/MS, while the FBXO44/PXR/P-gp signaling was investigated using Western blotting, immunofluorescence, ubiquitination assays, molecular docking, molecular dynamics simulations, and microscale thermophoresis (MST).
RESULTS
FSGT maintained superior anti-RA efficacy while markedly mitigating AA-induced nephrotoxicity. Pharmacokinetically, FSGT accelerated the clearance and urinary excretion of toxic diester diterpenoid alkaloids, reducing their renal accumulation. Mechanistically, FSGT suppressed E3 ubiquitin ligase FBXO44 expression, inhibited FBXO44-mediated PXR ubiquitination/degradation, promoted PXR expression, and upregulated P-gp efflux transporter expression. Verapamil abolished this protective effect. 18α-glycyrrhetinic acid and kaempferol were confirmed as key active components directly binding FBXO44.
CONCLUSION
FSGT reduces nephrotoxicity via FBXO44/PXR/P-gp signaling to accelerate toxic aconite alkaloids excretion, providing a scientific basis for "detoxification by compatibility" and preclinical mechanistic support for the safety profile of FSGT.
Jia-Hui Liu, Fei-Fei Liu, Li-Li Hong et al.· Journal of Ethnopharmacology· 0 citations
ETHNOPHARMACOLOGICAL RELEVANCE
Sinopodophyllum hexandrum (Royle) T.S. Ying fruit (SHF) is recorded in the Chinese Pharmacopoeia as a Tibetan medicine for regulating menstruation and promoting blood circulation. Although its pharmacological potential (e.g., anticancer, hypolipidemic) is recognized, little is known about the subacute toxicity and the associated mechanisms, especially in relation to gut microbiota, which is crucial for evaluating its safety.
AIM OF THE STUDY
This study evaluated the potential toxicological effects and underlying mechanisms behind SHF-induced subacute toxicity.
MATERIALS AND METHODS
Mice were orally administered SHF at doses of 80 or 250 mg/kg/day for 60 consecutive days. Changes in body-weight, histopathological and biochemical indices, intestinal microbiota and antioxidant factors were examined.
RESULTS
The low dose (80 mg/kg/day) was well-tolerated and induced the enrichment of short-chain fatty acid-producing bacteria (i.e., Ileibacterium, Romboutsia, and Erysipelotrichaceae) without apparent toxicity. In contrast, the high dose (250 mg/kg/day) caused significant weight loss, reversible pulmonary hyperinflation, hepatocellular injury, and tubular necrosis and focal interstitial inflammation with elevated blood urea nitrogen (BUN), indicating organ toxicity. Nevertheless, it also enhanced the colonic mucus barrier by expanding butyrate-producing consortia within Clostridia, Lachnospirales, and Ruminococcaceae while decreasing the abundance of Akkermansia and Bifidobacterium. Concurrently, upregulation of hepatic Nrf2/SOD1 suggested activated antioxidant responses, concomitant with ongoing tissue repair.
CONCLUSION
The effects of SHF were dose-dependent. The low dose demonstrates a safe and prebiotic profile, supporting its potential development as a functional food. Conversely, the high dose is associated with toxicity risks, necessitating pulmonary, liver and renal monitoring. Future research should determine the minimum effective dose to balance efficacy and safety for clinical translation.
Jian Han, Wei-Hua Zhao, Xiao Ma et al.· Journal of Ethnopharmacology· 0 citations
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