Aristolactam I (AL-I), as a metabolite of AA-I, exhibits toxicity that remains a subject of significant debate. AL-I exhibits detectable distribution in both traditional Chinese medicines and environmental samples. Therefore, understanding the safety of AL-I, particularly its long-term toxicity, is crucial. The detection rate of AL-I were detected in wheat samples obtained from Serbia was 100%, with a maximum concentration of 0.409 ng/g, cumulative exposures could matter. In long-term toxicity testing, no animals in AL-I groups died. At week 24 administration, no pathological changes similar to AA-I group were found in AL-I-H group. However, mild renal tubular injury was observed in discontinuation period. Localized mild renal interstitial collagen deposition was noted in 80% kidneys at weeks 50 discontinuation, but no pathological changes were observed in other tissues and AL-I-L group. Additionally, results of bone marrow micronucleus assay for AL-I-H group were negative, and no SNP mutation changes were observed in kidney/liver/stomach tissues compared with the control. A variety of metabolites were detected in AA-I group, including intermediates with carcinogenic risks. However, the metabolites in AL-I group were only AL-Ia and its glucuronide/sulfated derivatives, and AL-I was not detected in kidneys. We infer the nephrotoxicity of AL-I is much lower than that of AA-I, and no obvious tumorigenic or mutagenic effects were observed, which could be associated with metabolism in the body. Meanwhile, AL-I accumulation in environmental samples from Balkan region does not reach levels associated with nephrotoxicity, suggesting minimal toxicological risk. However, it is essential to control dosage and duration of use when applying medicines containing AL-I in clinical practice.

BACKGROUND:Chronic atrophic gastritis (CAG) is a common chronic digestive disorder associated with the occurrence and development of gastric cancer (GC). Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang (Fructus evodiae) is a traditional Chinese medicinal material often used to treat gastrointestinal diseases. However, the therapeutical effects of Fructus evodiae in CAG and underlying mechanisms remain unelucidated. PURPOSE:This study aimed to determine the efficacy of the water decoction of fructus evodiae in the treatment of CAG, reveal its mechanism of action, clarify its pharmacological material basis and regulatory pathways in the treatment of CAG, and provide a scientific basis for the clinical treatment of CAG with fructus evodiae. METHOD:First, we established CAG rat model and administered fructus evodiae decoction for treatment, monitoring serum inflammatory factors, hormones, and histopathology. Then, components of fructus evodiae decoction were determined using UHPLC-Q Exactive Orbitrap HRMS. Subsequently, the mechanism of fructus evodiae in the treatment of CAG were explored by proteomics analysis, network pharmacology and molecular docking. Finally, in vivo and in vitro validation was taken by western blot (WB) assays, ELISA, CCK-8, immunofluorescence staining, hematoxylin and eosin (HE) measurement, bile acid (BAs) analysed. RESULTS:Data showed that 25 compounds were identified in fructus evodiae decoction. The proteomics analysis, network pharmacology, and molecular docking results showed evodiamine (EVO) is a major active ingredient and PI3K/AKT/NF-κB pathway and gastrointestinal motility are key regulating pathways in fructus evodiae decoction used to treat CAG. In vivo and in vitro experiments confirmed that Fructus evodiae decoction and EVO significantly reduced the expression levels of IL-1β, IL-6, TNF-α, Gastrin-17 (G-17), somatostatin (SS), caudal type homeobox 2 (CDX2), and mucin 2 (MUC2) protein by inhibited PI3K/AKT/NF-κB signaling. Moreover, fructus evodiae decoction and EVO increased the expression of the gastrointestinal excitatory neurotransmitters ACh and 5-HT, promoted gastric emptying rate and small intestinal propulsion rate, and reduced the level of BAs in the stomach, thereby reducing further damage to the gastric mucosa. CONCLUSION:Fructus evodiae decoction exerts anti-CAG effects primarily by suppressing chronic inflammation and intestinal metaplasia through inhibition of the PI3K/AKT/NF-κB signaling pathway, thereby reducing bile acid accumulation and restoring gastrointestinal function. Importantly, evodiamine was identified as a key bioactive alkaloid of Fructus evodiae and was further validated as a critical mediator of these effects via targeted in vivo and in vitro experiments. By integrating proteomics, network pharmacology, molecular docking, and single-compound mechanistic validation, this study establishes evodiamine-centered regulation of the PI3K/AKT/NF-κB axis as a unifying mechanism underlying the therapeutic action of Fructus evodiae in MNNG-induced chronic atrophic gastritis.

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.

Curcuma is a traditional Chinese medicine that has been utilized for centuries in the treatment of various diseases. Terpenoids, particularly monoterpenes and sesquiterpenes, constitute the primary bioactive components of the essential oil derived from Curcuma species. Among these, curdione-one of the key active constituents-has been identified in 25 Curcuma species, with the highest concentration reported in the rhizome essential oil of Curcuma trichosantha Gagnep. Curdione can also be synthesized through chemical methods, and its regio- and stereo-selectivity can be further optimized via chemo-bio transformations. This compound demonstrates significant therapeutic potential, including anticancer, anti-thrombotic, anti-inflammatory, anti-viral, anti-fungal, anti-diabetic, and multi-organ protective properties. Despite these promising biological activities, its clinical application is hindered by poor water solubility and potential toxicity. This review summarizes current knowledge on the natural sources, chemical synthesis, chemo-bio transformations, metabolism, pharmacokinetics, pharmacological effects, potential toxicities, and molecular mechanisms of curdione. Furthermore, perspectives on future drug development are discussed with the aim of promoting the clinical translation of this promising natural compound.

ETHNOPHARMACOLOGICAL RELEVANCE:Aristolochiae Fructus (AF) is a "notable" Traditional Chinese Medicines (TCM), renowned for its efficacy in clearing lung heat, descending qi, relieving cough and asthma, as well as its well-documented toxicity. Traditionally used for conditions such as lung heat with cough and dyspnea, and hemorrhoidal swelling and pain, modern pharmacological research has uncovered additional potential clinical applications. However, in-depth studies have revealed that its constituent aristolochic acid I (AA-I) possesses potent nephrotoxicity and carcinogenicity, which poses a serious challenge and a fundamental constraint to its clinical application and related research. OBJECTIVE:This study evaluated the hepatorenal toxicity of chronic Aristolochiae Fructus aqueous extract (AFE) exposure in rats, profiled in vivo aristolochic acid metabolites, and identified proteomic biomarkers and pathways. A parallel comparison with equimolar AA-I revealed distinct and shared mechanisms between the whole herb and its isolated constituent. METHOD:Sprague-Dawley (SD) rats were orally administered AFE (0.95, 3.75, or 15.0 g/kg/day) or AA-I (0.7 mg/kg/day, equivalent to the AA-I content in the high-dose AFE group(AFE-H)) for 26 weeks, followed by a 4-week recovery period. Animals were euthanized at 13 and 26 weeks of treatment and after recovery for a comprehensive toxicological assessment, including relative organ-to-body weight ratios, serum biochemistry (ALT, AST, ALP, BUN, CRE), and histopathology of liver and kidney. Furthermore, aristolochic acids (AAs) metabolites in serum, liver, kidney, urine, and feces were qualitatively profiled by UPLC-Q-TOF MS. Based on these findings, integrated DIA/TMT-based proteomics, combined with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and STRING-based Protein-protein interaction (PPI) network analysis, identified hub proteins and key dysregulated pathways. These analyses revealed both shared and distinct mechanisms underlying AFE-H and AA-I-induced hepatorenal injury. Collectively, these findings provide robust mechanistic evidence demonstrating that the toxicity of the whole herb (Aristolochiae Fructus) cannot be fully extrapolated from studies on its isolated constituent (AA-I). RESULTS:Rats tolerated to AFE and AA-I well, with no treatment-related alterations in serum biochemistry or liver/kidney-to-body weight ratios. Histopathology revealed only mild and non-progressive renal tubular epithelial degeneration and periglomerular fibroblast proliferation in some rats of the AFE-H and AA-I groups, without classic features of aristolochic acid nephropathy (e.g., glomerular atrophy or basement membrane thickening). Lesions were absent in the low-dose AFE group (AFE-L) and medium-dose AFE group (AFE-M) and showed no recovery or worsening after a 4-week washout. No hepatic injury was observed in any group. Metabolite profiling detected no accumulation of AAs or their metabolites in liver or kidney tissues. AAs were predominantly excreted via feces, with significantly lower systemic exposure (serum/urine) observed in AFE-treated rats. Compared to AA-I, high-dose AFE markedly enhanced fecal formation of multiple AA metabolites (including AL-Ia + glu, AL-Ia, 7OH-AL-I, and AL-Ia-SO3), suggesting potent gut-mediated metabolic modulation. DIA proteomics identified 133 shared hepatic and 94 shared renal differentially expressed proteins (DEPs) between AFE-H and AA-I groups. Global expression patterns were largely concordant; however, key DEPs differed in their magnitude or direction of regulation, particularly those linked to hepatic metabolism, oxidative stress, immune response, glomerular filtration, and mitochondrial function. GO/KEGG analyses revealed overall functional similarity, with pathway activity differences: AA-I exhibited stronger enrichment in glomerular filtration and tRNA methylation (suggesting hepatic stress that may affect renal function), whereas AFE exhibited enhanced enrichment in steroid metabolism and defense against Gram-positive bacteria-likely mitigating endocrine- and infection-related renal risk. PPI network analysis revealed common hub proteins involved in hepatic immunity and renal DNA repair, alongside treatment-specific functional clusters, highlighting both shared and distinct mechanisms of AFE and AA-I action. CONCLUSION:Our study demonstrates that long-term administration of AFE (up to 15 g/kg/day) and an equivalent dose of AA-I induced no significant toxicity in rats under the specific experimental conditions, no significant toxicity was detected, however, given the established carcinogenicity of AA-I, extreme caution is warranted in any clinical context involving AA-I-containing herbs. AL-Ia in urine and feces could serve as a sensitive metabolic biomarker for dynamic monitoring of aristolochic acid exposure, and multiple constituents in AFE may accelerate AL-I metabolism. Proteomic analysis revealed that DEPs with the greatest divergence and functional relevance between the AFE-H and AA-I groups were primarily enriched in pathways related to glomerular filtration and energy metabolism, suggesting that their differences may reflect a "functional compensation-injury" state in renal tissue. AFE modulates hepatic 'immune-metabolic' and renal 'detoxification-repair' axes, mitigating AA-I-induced toxicity.

Background: Xiebai San (XBS), a classical Traditional Chinese Medicine formula comprising Cortex mori, Lycii Radicis Cortex, and Glycyrrhizae Radix et Rhizoma, has long been used for pulmonary inflammatory disorders. However, its underlying mechanisms remain un-clear. This study aimed to investigate the mechanisms by which XBS alleviates allergic pulmonary inflammation. Methods: Two murine models were established, consisting of a chronic ovalbumin (OVA)-induced model simulating adaptive immune responses and an acute compound 48/80-induced model triggering non-IgE-dependent mast cell activation. Pharmacodynamic indices including serum IgE, histamine, inflammatory cytokines, leukocyte profiles, and lung histopathology were evaluated. Network pharmacology was employed to predict core pathways. Arachidonic acid metabolites (AAMs) in lung tissues were quantified by targeted UPLC-MS/MS, and p38 MAPK signaling proteins were assessed by Western blot. Results: XBS significantly alleviated lung injury in both models. In the chronic OVA-induced model, XBS significantly reduced serum immunoglobulin E levels and inflammatory cell infiltration. In the acute model, XBS suppressed histamine release and mast cell-mediated inflammatory responses. Targeted metabolomics revealed differential regulatory mechanisms: XBS reduced lipoxygenase-derived metabolites, including leukotrienes and 12-hydroxyeicosatetraenoic acid in chronic inflammation, while suppressing cyclooxygenase-related prostaglandins in acute inflammation. Network pharmacology analysis identified arachidonic acid (AA) metabolism as a potential central pathway. The p38 mitogen-activated protein kinase pathway was partially involved. Conclusions: XBS effectively alleviates both chronic and acute allergic pulmonary inflammation through differential modulation of AA metabolism, providing mechanistic insights supporting its traditional use in allergic airway diseases.

This study aimed to elucidate the mechanism of Shenmai Injection(SMI) in inducing immediate hypersensitivity reaction by activating the Ras homolog gene family member A(RhoA)/Rho-associated coiled-coil forming protein kinase(ROCK) signaling pathway. In the in vivo experiment, ICR mice were randomly divided into a negative control group, SMI groups of low-dose(7.5 mL·kg~(-1)), medium-dose(15 mL·kg~(-1)), and high-dose(30 mL·kg~(-1)), as well as a positive control group. The effect of SMI on vascular leakage was detected by mouse auricular blue staining, and histopathological changes in the lung tissue were observed. In the in vitro experiment, the effect of SMI on the vascular endothelial barrier and cytoskeleton was evaluated by endothelial monolayer permeability assays and phalloidin staining. Western blot was employed to measure changes in the key protein expressions of the RhoA/ROCK signaling pathway, including phospho-myosin light chain 2(p-MLC2), myosin light chain 2(MLC2), phospho-myosin phosphatase target subunit 1(p-MYPT1), myosin phosphatase target subunit 1(MYPT1), guanosine triphosphate-RhoA(GTP-RhoA), and total RhoA, in endothelial cells as well as in mouse ear and lung tissues after SMI administration. To verify the role of the RhoA/ROCK signaling pathway in SMI-induced immediate hypersensitivity reactions, mice were pretreated with the ROCK inhibitor fasudil to observe the vascular hyperpermeability induced by SMI. The results showed that SMI caused a dose-dependent increase in ear vascular permeability in ICR mice, with the 30 mL·kg~(-1) dose group exhibiting marked ear vascular extravasation and slight alveolar wall thickening, while resulting in concentration-dependent endothelial barrier function decrease and cytoskeleton changes. Mechanistically, SMI could significantly upregulate GTP-RhoA/RhoA, p-MLC2/MLC2, and p-MYPT1/MYPT1 levels in vascular endothelial cells, as well as in mouse ear and lung tissues. Additionally, the ROCK inhibitor fasudil could significantly reduce the SMI-induced vascular hyperpermeability, indicating the key role of the RhoA/ROCK signaling pathway in SMI-induced hypersensitivity reactions. The results suggest that the risk of SMl-induced immediate hypersensitivity reactions may be associated with excessively high doses or rapid administration, and that the RhoA/ROCK signaling pathway plays an important role in this response.

This study aimed to investigate the mechanism of dihydroartemisinin(DHA)in ameliorating multiple sclerosis(MS).Hematoxylin and eosin(HE)staining was used to assess inflammatory cell infiltration,while luxol fast blue(LFB)staining and electron microscopy were performed to evaluate myelin sheath structure.In cell experiments,this study measured programmed cell death ligand 1(PD-L1)expression on BV2 cells and forkhead box protein p3(Foxp3)expression in Jurkat T cells co-cultured with BV2 cells,determined the C-C motif chemokine ligand 5(CCL5)concentration in the supernatant of BV2 cells,and evaluated BV2 cell chemotaxis.Western blot(WB)was performed to detect protein levels of receptor tyrosine kinase(AXL),phosphorylated AXL(p-AXL),signal transducer and activator of transcription 1(STAT1),phosphorylated STAT1(p-STAT1),and suppressors of cytokine signaling 3(SOCS3).To confirm the role of AXL,key cellular assays were repeated following inhibition of AXL.Additionally,under physiological conditions,the effects of DHA on body weight,spleen weight,and peripheral blood immune cell profiles were examined.The results showed that DHA significantly reduced disease scores,attenuated body weight loss,suppressed inflammatory infiltration,and promoted myelin sheath repair in experimental autoimmune encephalomyelitis(EAE)mice.At the cellular level,DHA upregulated PD-L1 expression on BV2 cells and Foxp3 expression in co-cultured Jurkat cells,and inhibited CCL5 release and BV2 cell chemotaxis.It also upregulated AXL,p-AXL,p-STAT1,and SOCS3 protein expression in BV2 cells.When AXL was inhibited,these effects are nullified.In healthy mice,DHA did not have any effect on their various parameters.In conclusion,DHA maintains inflammatory homeostasis in the EAE model by activating the AXL signaling pathway in microglia.

Background: Mucosal healing is a major clinical challenge and a critical prognostic factor in inflammatory bowel disease (IBD). Achieving mucosal healing requires the functional reprogramming of macrophages to facilitate intestinal stem cells (ISCs)-mediated repair, a process impaired in IBD due to dysregulated macrophage activity. Dihydroartemisinin (DHA), a derivative of artemisinin, shows promise in treating IBD, but its therapeutic potential remains underexplored due to its common classification as an anti-inflammatory agent. Purpose: This study aims to evaluate the efficacy of DHA in promoting mucosal healing in IBD and to elucidate the underlying mechanisms of macrophage reprogramming, thereby expanding the therapeutic potential of DHA beyond its conventional anti-inflammatory actions. Methods: The therapeutic efficacy of DHA and its underlying mechanisms were systematically investigated using a DSS-induced colitis mouse model, with a focus on the repair phase. Mucosal healing was assessed through comprehensive histopathological and functional evaluations. DHA's role in macrophage metabolic reprogramming was explored through transcriptomic and metabolic analyses, and its effect on epithelial regeneration was examined using macrophage-organoid co-cultures. A molecular target discovery approach, integrating Mendelian randomization, molecular docking, and direct binding assays, identified 11(3HSD-1 as a molecular target of DHA, which was subsequently confirmed through genetic and pharmacological loss-of-function studies in macrophages. Results: Our findings demonstrated that DHA significantly promoted mucosal healing in a DSS-induced colitis model during the repair phase, as evidenced by reduced disease activity scores, increased colon length, and decreased histological damage. DHA also facilitated the recovery of gut functions, including barrier integrity, absorption, secretion, and motility. Macrophages were found to be essential for therapeutic effects of DHA. Specifically, DHA reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, inducing a pro-repair phenotype characterized by enhanced secretion of Relm alpha and Wnt3a, which promoted the proliferation and differentiation of intestinal organoids. Mechanistically, we found that DHA directly bound to and activated 11 beta HSD-1, a key metabolic regulator in macrophages. This activation triggered STAT3/6 signaling, establishing a positive feedback loop that reinforced metabolic remodeling and facilitated the release of repair-promoting factors. Conclusion: Our findings demonstrate that DHA promotes intestinal mucosal healing by reprogramming macrophage metabolism, thereby enhancing ISC proliferation and differentiation. These results provide new insights into the potential of DHA in reshaping immune homeostasis, offering promising therapeutic strategies for IBD.

ETHNOPHARMACOLOGICAL RELEVANCE:In recent years, with more widespread use of traditional Chinese medicine (TCM) and continuous improvement of adverse drug reaction monitoring systems, reports of liver injury caused by TCMs, natural drugs, and related formulations are increasing and attracting broad attention. Investigating the characteristics involved in TCM-induced liver injury, understanding the underlying mechanisms correlated and scientifically assessing the potential hepatotoxicity are crucial for enhancing the safety of TCMs in clinical use. AIM OF THE STUDY:This review aims to show the characteristics of TCM-induced liver injury recorded in clinical reports, and summarize the underlying mechanisms and predictive technologies involved in TCM-induced hepatotoxicity. METHODS:Literature of clinical reports, mechanisms investigating and predictive technologies related with TCM-induced liver injury was retrieved from multiple databases (CBM, CNKI, PubMed, Wanfang Data, Web of Science, and Google Scholar), as well as doctoral and master's theses and official websites, covering publications from 1982 to 2025. RESULTS:Through literature review, 481 articles reporting 571 cases of TCM-induced liver injury were collected and descriptively summarized. 265 TCMs were reported, with single TCM herb accounting for 26.97 % and TCM herb formulas for 73.03 %. Hepatocellular injury was the most common type of liver damage. Among the reported TCMs, Polygonum multiflorum Thunb., Psoralea corylifolia L. and Gynura japonica Thunb. Juel were most frequently documented. The mechanisms related to TCM-induced liver injury mainly included mitochondrial dysfunction, endoplasmic reticulum stress, bile acid homeostasis disruption, gut microbiota dysbiosis, CYP450 enzyme metabolic abnormalities, and idiosyncratic immune responses. CONCLUSION:This review summarizes TCMs that are most frequently reported in published cases of liver injury and outlines the major underlying mechanisms involved. Although current regulatory guidelines mandate hepatotoxicity evaluation of TCMs, predictive approaches remain imperfect. Emerging models such as organoids and computational tools are being explored to address these limitations, with the aim of improving clinical applicability through more accurate risk prediction and mechanistic investigation.

ETHNOPHARMACOLOGICAL RELEVANCE:Psoraleae Fructus (PF), the dried mature fruit of the leguminous plant Psoralea corylifolia L., is often used as a nutraceutical and to treat ulcerative colitis (UC). However, recently there have been reports of PF-induced liver injury. AIM OF THE STUDY:To investigate the difference and mechanism of hepatotoxicity between normal and UC rats oral administration with PF, and clarify the relationship between PF risk and disease status. MATERIALS AND METHODS:PF water extracts (at the human equivalent dosage and 8-fold greater; 0.7 and 5.6 g/kg/day, respectively) were given to normal and UC rats for 4 weeks, and the general behaviors and colonic mucosal conditions were observed. The liver injury and its mechanism were studied by blood biochemistry, coagulation time, liver hematoxylin and eosin (H&E) staining, bile acids (BAs) metabolism, transcriptomics analysis, quantitative real-time polymerase chain reaction (qRT‒PCR) and Western blot (WB)experiments. RESULTS:Normal rats receiving 5.6 g/kg PF water extract showed significantly increased serum levels of total bilirubin (TBIL) and total bile acids (TBA), significantly prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT), and slightly swollen hepatocytes, and obvious hepatobiliary hyperplasia. These liver injuries may be related to disordered BAs metabolism: the levels of farnesoid x receptor (FXR) and sulfotransferase family 2A member 1 (SULT2a1) were down-regulated, whereas the levels of microsomal epoxide hydrolase (mEH), organic anion transporting polypeptide (OATP) and multidrug resistance-associated protein 3 (MRP3) were up-regulated, leading to liver and blood UnconBA and GlycineBA accumulation. However, at the same dose, UC model rats exhibited no obvious liver damage. CONCLUSION:Normal rats, but not UC rats, displayed signs of liver injury in response to 5.6 g/kg PF water extract administration. Therefore, we recommend that healthy individuals should be aware of the potential risks associated with PF, and other patients should take PF according to their physician's guidance.

BACKGROUND:Geniposide (GE) has potential efficacy in treating ulcerative colitis (UC). However, its reactivity can be affected by rapid degradation after oral administration. Furthermore, increasing oral doses may lead to hepatotoxicity. Thus, We used enema administration, characterized by smaller dose and higher localized concentration in the lesion, to improve the above situation. PURPOSE:We aimed to confirm that enema administration is a better modality than oral administration for GE against UC and to explore its mechanism. STUDY DESIGN/METHOD:We established UC mouse model, monitoring Disease Activity Index (DAI), inflammatory cytokines levels, and histopathology. Macrogenomics and bile acid (BAs) metabolomics analysed the major intestinal flora and BAs. Simultaneouslly, we conducted quantitative proteomics analysis and screened core proteins and pathway. In vitro validation was taken by qPCR, immunofluorescence and immunoblotting experiments. RESULTS:GE via enema alleviate UC by inhibiting inflammatory factor production through downregulating S100A8/S100A9/NF-κB pathway. Analysis of the intestinal flora and BAs revealed that the enhanced abundance of Lachnospiraceae, which improves the ratio of primary to secondary BAs, and the reduced abundance of Provocaceae, which increases intestinal permeability and promotes inflammation, favored the restoration of the intestinal barrier. In addition, in vitro experiments confirmed that the key BA metabolites (mainly UDCA, DCA, and LCA) stimulated TGR5 signal to inhibit the assembly of the NLRP3 inflammasome and alleviated inflammation. CONCLUSION:We firstly confirmed that GE alleviates UC via the enema route in a better manner than the oral route, through enhancing the intestinal barrier, restoring intestinal flora and BAs homeostasis, and inhibiting inflammatory injury. This study initially revealed that GE can alleviate UC through elevating UDCA, DCA, and LCA levels at the colonic site to activate TGR5 receptor for inhibiting the NLRP3 inflammasome, in addition to downregulating the S100A8/S100A9/-TLR4-NF-κB pathway related inflammatory response directly. The evidences offer a promising strategy and profround meaning for UC treatment.

Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.

In this study, lipopolysaccharide(LPS), ovalbumin(OVA), and compound 48/80(C48/80) were administered to establish non-infectious pneumonia models under simulated clinical conditions, and the correlation between their pathological characteristics and traditional Chinese medicine(TCM) syndromes was compared, providing the basis for the selection of appropriate animal models for TCM efficacy evaluation. An acute pneumonia model was established by nasal instillation of LPS combined with intraperitoneal injection for intensive stimulation. Three doses of OVA mixed with aluminum hydroxide adjuvant were injected intraperitoneally on days one, three, and five and OVA was administered via endotracheal drip for excitation on days 14-18 to establish an OVA-induced allergic pneumonia model. A single intravenous injection of three doses of C48/80 was adopted to establish a C48/80-induced pneumonia model. By detecting the changes in peripheral blood leukocyte classification, lung tissue and plasma cytokines, immunoglobulins(Ig), histamine levels, and arachidonic acid metabolites, the multi-dimensional analysis was carried out based on pathological evaluation. The results showed that the three models could cause pulmonary edema, increased wet weight in the lung, and obvious exudative inflammation in lung tissue pathology, especially for LPS. A number of pyrogenic cytokines, inclading interleukin(IL)-6, interferon(IFN)-γ, IL-1β, and IL-4 were significantly elevated in the LPS pneumonia model. Significantly increased levels of prostacyclin analogs such as prostaglandin E2(PGE2) and PGD2, which cause increased vascular permeability, and neutrophils in peripheral blood were significantly elevated. The model could partly reflect the clinical characteristics of phlegm heat accumulating in the lung or dampness toxin obstructing the lung. The OVA model showed that the sensitization mediators IgE and leukotriene E4(LTE4) were increased, and the anti-inflammatory prostacyclin 6-keto-PGF2α was decreased. Immune cells(lymphocytes and monocytes) were decreased, and inflammatory cells(neutrophils and basophils) were increased, reflecting the characteristics of "deficiency", "phlegm", or "dampness". Lymphocytes, monocytes, and basophils were significantly increased in the C48/80 model. The phenotype of the model was that the content of histamine, a large number of prostacyclins(6-keto-PGE1, PGF2α, 15-keto-PGF2α, 6-keto-PGF1α, 13,14-D-15-keto-PGE2, PGD2, PGE2, and PGH2), LTE4, and 5-hydroxyeicosatetraenoic acid(5S-HETE) was significantly increased, and these indicators were associated with vascular expansion and increased vascular permeability. The pyrogenic inflammatory cytokines were not increased. The C48/80 model reflected the characteristics of cold and damp accumulation. In the study, three non-infectious pneumonia models were constructed. The LPS model exhibited neutrophil infiltration and elevated inflammatory factors, which was suitable for the efficacy study of TCM for clearing heat, detoxifying, removing dampness, and eliminating phlegm. The OVA model, which took allergic inflammation as an index, was suitable for the efficacy study of Yiqi Gubiao formulas. The C48/80 model exhibited increased vasoactive substances(histamine, PGs, and LTE4), which was suitable for the efficacy study and evaluation of TCM for warming the lung, dispersing cold, drying dampness, and resolving phlegm. The study provides a theoretical basis for model selection for the efficacy evaluation of TCM in the treatment of pneumonia.

Background:Psoralea corylifolia L.(Buguzhi,BGZ),known for its efficacy in supporting pregnancy and preventing miscarriage,has been used in China for over 1000 years.Recently,BGZ has been identified as a potential cause of drug-induced liver injury.However,its safety during pregnancy remains unclear,which significantly hinders its routine clinical application. Objective:To investigate the effects of BGZ administration during pregnancy on the liver of mouse mothers and their weaned 21-day-old offspring. Methods:Mice were orally administered BGZ at doses of 2.5 and 10 g/kg during pregnancy,with BGZ withdrawal during the lactation period.Liver histopathology(hematoxylin-eosin staining),biochemical analysis,and evaluation of liver bile acid metabolism were per-formed after the lactation period. Results:BGZ administration at doses of 2.5 and 10 g/kg during pregnancy,followed by withdrawal during the lactation period,caused mild liver damage in both mothers and their 21-day-old offspring.Serum total bile acid(TBA)levels were elevated compared with those in the control group.Additionally,changes were observed in the levels and proportions of various bile acids(BAs)in the liver,suggesting mild effects on BA metabolism. Conclusion:BGZ administration during pregnancy caused mild liver damage and increased serum TBA levels in both mouse mothers and their 21-day-old offspring.This phenomenon may be associated with imbalanced BA metabolism in the liver.Based on the present study and the limited toxicological research on BGZ,pregnant women should avoid prolonged use of BGZ.If BGZ is administered dur-ing pregnancy,serum TBA levels should be monitored,and if elevated,BGZ should be discontinued.

The penetration of nanocarriers across the blood-brain barrier (BBB) through transcellular transcytosis is difficult owing to their lysosomal degradation after endocytosis. This obstacle prevents the targeted delivery of siRNAs in the treatment of glioma or other brain diseases. In this study, endoplasmic reticulum (ER) membranes derived from glioma cells were used to fabricate the integrative hybrid nanoplexes (EhCv/siRNA NPs) for enhancing the penetration efficiency of crossing BBB through transcytosis. Compared to undecorated Cv/siRNA NPs, the ER membrane-decorated EhCv/siRNA NPs evaded lysosomal degradation through a non-degradable endosome-Golgi/ER pathway, resulting in a significantly stronger ability to cross the BBB through transcellular transcytosis and better gene-silencing effects of siRNAs in U87 glioma in vitro and in vivo. Altogether, this study is valuable for designing the optimized non-degradable transcellular transcytosis across the blood-brain barrier and advancing drug delivery to brain.