Total cucurbitacins from Herpetospermum pedunculosum pericarp do better than Hu-lu-su-pian (HLSP) in its safety and hepatoprotective efficacy.

The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.

Study on the acute toxicity of trichlorfon and its breakdown product dichlorvos to goldfish (Carassius auratus) based on 1H NMR metabonomics.

Trichlorfon, one of the most widely used organophosphate insecticides, is commonly employed in aquaculture and agriculture to combat parasitic infestations. However, its inherent instability leads to rapid decomposition into dichlorvos (DDVP), increasing its toxicity by eightfold. Therefore, the environmental effects of trichlorfon in real-world scenarios involve the combined effects of trichlorfon and its degradation product, DDVP. In this study, we systematically investigated the degradation of trichlorfon in tap water over time using HPLC and LC-MS/MS analysis. Subsequently, an experiment was conducted to assess the acute toxicity of trichlorfon and DDVP on goldfish (Carassius auratus), employing a 1H NMR-based metabolic approach in conjunction with serum biochemistry, histopathological inspection, and correlation network analysis. Exposure to trichlorfon and its degradation product DDVP leads to increased lipid peroxidation, reduced antioxidant activity, and severe hepatotoxicity and nephrotoxicity in goldfish. Based on the observed pathological changes and metabolite alterations, short-term exposure to trichlorfon significantly affected the liver and kidney functions of goldfish, while exerting minimal influence on the brain, potentially due to the presence of the blood-brain barrier. The changes in the metabolic profile indicated that trichlorfon and DDVP influenced several pathways, including oxidative stress, protein synthesis, energy metabolism, and nucleic acid metabolism. This study demonstrated the applicability and potential of 1H NMR-based metabonomics in pesticide environmental risk assessment, providing a feasible method for the comprehensive study of pesticide toxicity in water environments.

Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Torachrysone-8-O-ß-d-glucoside mediates anti-inflammatory effects by blocking aldose reductase-catalyzed metabolism of lipid peroxidation products.

Aldose reductase (AR) is an important enzyme involved in the reduction of various aldehyde and carbonyl compounds, including the highly reactive and toxic 4-hydroxynonenal (4-HNE), which has been linked to the progression of various pathologies such as atherosclerosis, hyperglycemia, inflammation, and tumors. AR inhibitors have potential therapeutic benefits for these diseases by reducing lipid peroxidation and mitigating the harmful effects of reactive aldehydes. In this study, we found that torachrysone-8-O-ß-d-glucoside (TG), a natural product isolated from Polygonum multiflorum Thunb., functions as an effective inhibitor of AR, exhibiting potent effects in clearing reactive aldehydes and reducing inflammation. TG up-regulated the mRNA levels of several antioxidant factors downstream of NRF2, especially glutathione S-transferase (GST), which is significantly increased, thus detoxifying 4-HNE by facilitating the conjugation of 4-HNE to glutathione, forming glutathione-4-hydroxynonenal (GS-HNE). By employing a combination of molecular docking, cellular thermal shift assay, and enzyme activity experiments, we demonstrated that TG exhibited strong binding affinity with AR and inhibited its activity and blocked the conversion of GS-HNE to glutathionyl-1,4-dihydroxynonene (GS-DHN), thereby preventing the formation of protein adducts and inducing severe cellular damage. This study provides novel insights into the anti-inflammatory mechanisms of AR inhibitors and offers potential avenues for developing therapeutic strategies for AR-related pathologies. Our findings suggest that TG, as an AR inhibitor, may hold promise as a therapeutic agent for treating conditions characterized by excessive lipid peroxidation and inflammation. Further investigations are needed to fully explore the clinical potential of TG and evaluate its efficacy in the treatment and management of these complex diseases.

Chemical Constituents of the Deep-Sea-Derived Penicillium citreonigrum MCCC 3A00169 and Their Antiproliferative Effects.

Six new citreoviridins (citreoviridins J-O, 1-6) and twenty-two known compounds (7-28) were isolated from the deep-sea-derived Penicillium citreonigrum MCCC 3A00169. The structures of the new compounds were determined by spectroscopic methods, including the HRESIMS, NMR, ECD calculations, and dimolybdenum tetraacetate-induced CD (ICD) experiments. Citreoviridins J-O (1-6) are diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2-C-7. Pyrenocine A (7), terrein (14), and citreoviridin (20) significantly induced apoptosis for HeLa cells with IC50 values of 5.4 µM, 11.3 µM, and 0.7 µM, respectively. To be specific, pyrenocine A could induce S phase arrest, while terrein and citreoviridin could obviously induce G0-G1 phase arrest. Citreoviridin could inhibit mTOR activity in HeLa cells.

Metabolic response of earthworms (Pheretima guillemi) to silver nanoparticles in sludge-amended soil.

Silver nanoparticles (AgNPs) can enter soils via the application of sludge and pose risks to soil invertebrates. However, current knowledge regarding the toxicity of AgNPs at environmentally relevant concentration is insufficient, especially at the molecular level. Therefore, we examined the effects of low-level AgNPs (7.2 mg kg-1, dry weight) on the bioaccumulation, pathology and metabolism of earthworms (Pheretima guillemi). After exposure for 28 d, earthworms were dissected into digestive system and the rest of the body to explore the response of different body parts to AgNPs. Ag concentration in the digestive system of exposed group (2.5 mg kg-1, dry weight) was significantly higher than that of the control group (0.5 mg kg-1, dry weight). AgNPs exposure had no significant effects on the survival and growth, but induced intestinal damage and metabolic interference to earthworms relative to the control. Metabolomics analysis showed that AgNPs exposure disturbed the glycerophospholipid metabolism, glutathione metabolism and energy metabolism in the digestive system and the energy metabolism in the rest of the body. AgNPs exposure also induced lipid peroxidation in the digestive system. The different metabolic responses between two body parts highlighted the importance of the uptake routes of Ag. These results provide a biochemical insight for the risk assessment of low-level AgNPs in terrestrial environment.

Fe-MOGs-based enzyme mimetic and its mediated electrochemiluminescence for in situ detection of H2O2 released from Hela cells.

Enzyme mimetics have attracted wide interest due to their inherent enzyme-like activity and unique physicochemical properties, as well as promising applications in disease diagnosis, treatment and monitoring. Inspired by the attributes of nonheme iron enzymes, synthetic models were designed to mimic their capability and investigate the catalytic mechanisms. Herein, metal-organic gels (Fe-MOGs) with horseradish peroxidase (HRP) like Fe-NX structure were successfully synthesized though the coordination between iron and 1,10-phenanthroline-2,9-dicarboxylic acid (PDA) and exhibited excellent peroxidase-like activity. Its structure-activity relationship and the in-situ electrochemiluminescence (ECL) detection of H2O2 secreted by Hela cells were further investigated. The highly dispersed Fe-NX active sites inside Fe-MOGs were able to catalyze the decomposition of H2O2 into large amounts of reactive oxygen species (ROS) via a Fenton-like reaction under a low overpotential. Due to the accumulation of ROS free radicals, the luminol ECL emission was significantly amplified. A proof-of-concept biosensor was constructed with a detection limit as low as 2.2 nM and a wide linear range from 0.01 to 40 µM. As a novel metal organic gels based enzyme mimetic, Fe-MOGs show great promises in early cancer detection and pathological process monitoring.

Acute hepatotoxicity and nephrotoxicity risk assessment of the Tibetan medicine 25 flavors of the turquoise pill based on 1H-NMR metabonomics.

ETHNOPHARMACOLOGICAL RELEVANCE: 25 flavors of the turquoise pill, a traditional Tibetan medicine for the treatment of various types of hepatitis, has not been investigated on its safety, especially the component mineral turquoise, which is believed to be essential but worried for its potential toxicity. AIM OF THE STUDY: To explore the potential acute toxicity and function of 25 flavors of the turquoise pill and turquoise, the possible mechanism of the effects of turquoise and 25 flavors of the turquoise pill were systematically studied based on 1H NMR metabolomics. MATERIALS AND METHODS: The rats were administered with turquoise and 25 flavors of the turquoise pill by gavage for 7 days, and samples of serum, liver, and kidney were collected. The potential toxicity and function of turquoise and 25 flavors of the turquoise pill on the liver and kidney of SD rats were evaluated by 1H NMR metabonomics, histopathology, and biochemical indexes. RESULTS: The results demonstrated that 25 flavors of the turquoise pill could scavenge free oxygen radicals, strengthen aerobic respiration and inhibit glycolysis in the liver. It did not cause oxidative stress in the kidney with no obvious damage. By modulation of branched-chain amino acids (BCAAs), 25 flavors of the turquoise pill can improve the utilization of glucose and promote aerobic respiration of the kidney. CONCLUSION: Considering the high dosage and short duration used in this study relative to their typical clinical usage, administration of 25 flavors of the turquoise pill and its component mineral turquoise are safe to livers and kidneys.

NMR-based metabolomics approach to study the effects of Wu-Zi-Yan-Zong-Wan on triptolide-induced oligospermia in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Wu-Zi-Yan-Zong-Wan (WZYZW) is a commonly used Chinese medicinal recipe for oligozoospermia. Oligozoospermia is a common disease that harms human fertility, there is no effective therapeutic medicine at present. However, the underlying pharmacological mechanism remains unclear. METHODS: Oligozoospermia rats model induced by Tripterygium glycosides (TG) was established to inspect the efficiency of WZYZW in the treatment of oligozoospermia by traditional pharmacodynamics combined with NMR-based metabolomics. Multivariate statistics were used to extracted the underlying biomarkers and metabolic pathways of WZYZW in the treatment of oligozoospermia. RESULTS: The results showed that TG disturbed many metabolites and metabolic pathways such as oxidative stress (choline, O-phosphocholine, betaine and ascorbate), energy metabolism in mitochondria (glucose, lactate, succinate, fumarate, 3-hydroxybutyrate and alanine), mitochondrial apoptosis markers (Bax and Bcl-2) and amino acids metabolisms (arginine, branched-chain amino acids, taurine and myo-inositol). CONCLUSIONS: WZYZW could significantly reverse the disturbed metabolites to their normal status by their abilities of anti-oxidation, anti-apoptosis, balancing the osmotic pressure regulatory molecules and regulating the amino acids metabolism. This study provides pharmacological basis and guidance for the clinical usage of WZYZW.

Growth inhibition and metabolomic analysis of Xanthomonas oryzae pv. oryzae treated with resveratrol.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) can cause destructive bacterial blight in rice. As an antibacterial, resveratrol may inhibit Xoo growth. This study focused on the potential structural-activity relationship of resveratrol and its derivatives against Xoo growth, and 1H-NMR-based metabolomic analysis was applied to investigate the global metabolite changes in Xoo after resveratrol treatment. RESULTS: Resveratrol showed the strongest inhibitory effects on Xoo growth compared with its derivatives, which lacked double bonds (compounds 4-6) or hydroxyls were substituted with methoxyls (compounds 7-9). The IC50 of resveratrol against Xoo growth was 11.67 ± 0.58 µg/mL. Results indicated that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were vital for this inhibition. Interestingly, resveratrol also significantly inhibited Xoo flagellum growth. Based on 1H-NMR global metabolic analysis, a total of 30 Xoo metabolites were identified, the changes in the metabolic profile indicated that resveratrol could cause oxidative stress as well as disturb energy, purine, amino acid, and NAD+ metabolism in Xoo, resulting in the observed inhibitory effects on growth. CONCLUSIONS: This study showed that the double bond of resveratrol contributed to its inhibitory effects on Xoo growth, and hydroxyls were also the important active groups. Resveratrol could cause oxidative stress of Xoo cells, and disturb the metabolism of energy, purine, amino acid and NAD +, thus inhibit Xoo growth.

Therapeutic assessment of fractions of Gastrodiae Rhizoma on chronic atrophic gastritis by 1H NMR-based metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodiae Rhizoma (GR), a well-known and commonly-used TCM (Traditional Chinese Medicine) for treating headache, dizziness, tetanus, epilepsy, and etc., has been proven to relieve chronic atrophic gastritis (CAG). Due to its complex ingredients, the active fractions responsible for the treatment of CAG remain largely unknown. AIM OF THE STUDY: To explore the underlying material and interpret its underlying mechanism, the therapeutic effect of extract from different polar parts of Gastrodiae Rhizoma on autoimmune CAG was studied based on the 1H NMR metabolomics. MATERIALS AND METHODS: The rat model of CAG was established by autoimmune method. The modeled CAG rats were then treated with 4 polar parts (T1-4 in descending polarity, corresponding to water, n-butanol, ethyl acetate and petroleum ether extracts, respectively) of Gastrodiae Rhizoma for 21 consecutive days. The stomach and serum samples were collected and then subjected to histopathology observation, biochemical measurement (MDA, SOD, GSH, NO, XOD and pepsin), 1H NMR metabolic profiling and multivariate/univariate statistical analysis. RESULTS: The results showed that T1 had the best therapeutic effect, T2 the second, and T3 and T4 the poorest with no obvious therapeutic effect, demonstrating that the effective components of Gastrodiae Rhizoma should be compounds of high polarity. T1 achieved good therapeutic effects due to the anti-inflammatory and anti-oxidant activities, and by rectifying the disturbed energy and amino acid metabolism in CAG model. CONCLUSION: This integrated metabolomics approach proved the validity of the therapeutic effect of extract from different polar parts of Gastrodiae Rhizoma on autoimmune CAG, providing new insights into the underlying mechanisms, and demonstrating the feasibility of metabolomics to evaluate efficacy of herbal drug, which is often difficult by traditional means.

4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects.

Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

Alkaloids from the Branches and Leaves of Elaeocarpus angustifolius.

Nine new alkaloids, (+)-1, (-)-1, 2, (+)-3, (-)-3, and 4-7, along with five known compounds (8-12), were obtained from the branches and leaves of Elaeocarpus angustifolius. The alkaloids were structurally characterized by NMR and MS data. The absolute configurations of (+)-1, (-)-1, (+)-3, and (-)-3 were determined by comparing their experimental and computed electronic circular dichroism spectra. (±)-8,9-Dehydroelaeocarpine (5), (±)-9-epielaeocarpine cis-N-oxide trifluoroacetate (6), and (±)-elaeocarpine trifluoroacetate (9) exerted weak inhibitory activities against butyrylcholinesterase with IC50 values of 39, 29, and 35 µM, respectively, while that of tacrine, the positive control, was 0.07 ± 0.01 µM. This is the first report of the cholinesterase inhibitory activities of Elaeocarpus alkaloids.

Potential hepatoxicity risk of the shell of Herpetospermum caudigerum Wall in rats based on 1H-NMR metabonomics.

The Herpetospermum caudigerum Wall (HCW) is a traditional Tibetan medicine and is widely used in clinical practice. However, the shell of the HCW (SHCW) has rarely been studied, and some researchers have suggested that the SHCW may be toxic. Therefore, in this study, SHCW was administered to rats at two doses (0.1 and 0.33 g/kg) once a day for 21 days. The hepatic stimuli induced by SHCW in rats were investigated for the first time by 1H-NMR-based metabolomics combined with histopathological observation and biochemical detection. Histopathological sections showed a certain degree of hepatocyte edema and hepatic sinus congestion in the liver tissue of the rats in the drug-administered group. Serum biochemical indicators revealed a significant increase in ALT, AST, and MDA, and a significant decrease in SOD. Metabolomic results showed that the metabolites in rats were changed after gavage administration of extracts from SHCW. By multivariate statistical analysis and univariate analysis, it was found that SHCW could cause the disorder of energy metabolism, oxidative stress and amino acid metabolism in rats, leading to liver damage. This comprehensive metabolomics approach demonstrates its ability to describe the global metabolic state of an organism and provides a powerful and viable tool for exploring drug-induced toxicity or side effects.

Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis.

DT-13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT-13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis-related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non-muscle myosin IIA (NM IIA)-induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT-13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (-)002Dblebbistatin or MYH-9 shRNA, the synergistic inhibition effect of DT-13 and TPT on aerobic glycolysis was eliminated in BGC-823 cells. Immunohistochemical analysis revealed selective up-regulation of NM IIA while specific down-regulation of p-CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.

Metabolomic analysis of quorum sensing inhibitor hordenine on Pseudomonas aeruginosa.

Proton magnetic resonance-based metabolomics analysis was performed to determine the global metabolite changes in pathogenic bacterium Pseudomonas aeruginosa PAO1 following exposure to quorum sensing (QS) inhibitor hordenine. Pyocyanin inhibition assay confirmed that hordenine exhibited potent QS inhibitory activity. A total of 40 metabolites were assigned by PMR spectra. Hordenine treatment resulted in the destruction of QS system in P. aeruginosa PAO1 by downregulating the expressions of genes involved in QS. The synthesis of antioxidant enzymes was repressed and the oxidative stress was enhanced due to the dysfunctional QS system of P. aeruginosa PAO1. The enhanced oxidative stress induced by the dysfunctional QS system of P. aeruginosa PAO1 altered the membrane components, enhanced membrane permeability, and disturbed energy metabolism, amino acid metabolism, and nucleotide metabolism, and would ultimately attenuate the pathogenicity of P. aeruginosa PAO1. Hordenine may have promising potential for controlling nosocomial pathogens.

Inhibition of Quorum Sensing and Virulence in Serratia marcescens by Hordenine.

Serratia marcescens NJ01 is a pathogenic bacterium isolated from diseased tomato leaves. Here, we report on the development of a tomato- S. marcescens host-pathogen system as a model to evaluate the effects of hordenine on quorum sensing (QS)-mediated pathogenicity under native conditions. Exposure to hordenine at 25, 50, and 100 µg/mL significantly inhibited the production of acyl-homoserine lactones and the formation of biofilms. Hordenine treatment notably enhanced the susceptibility of the preformed biofilms to ciprofloxacin by reducing the production of extracellular polysaccharides, destroying the architecture of biofilms, and changing the permeability of membranes, as evidenced by the scattered appearance and dominant red fluorescence in the combination-treated biofilms. Furthermore, the addition of hordenine affected the production of virulence factors, influenced the intracellular metabolites, and downregulated the expressions of QS- and biofilm-related genes. The plant infection model indicated that hordenine could significantly attenuate the pathogenicity of S. marcescens NJ01 in tomato plants. Thus, hordenine could act as a potential pesticide or pesticide accelerant in treating crop infections.

Nuclear magnetic resonance-based metabolomics approach to evaluate preventive and therapeutic effects of Gastrodia elata Blume on chronic atrophic gastritis.

Chronic atrophic gastritis (CAG) is one of the most common digestive system diseases worldwide which defined by WHO as initial step of cancer. Gastrodia elata Blume (GEB) is a traditional herbal with multiple pharmacological activities which was widely used in Asian countries. This study aims to explore the preventive and therapeutical effects of Gastrodia elata Blume on auto-immune induced CAG in rats. Tissues of stomachs were collected and submitted to 1H NMR-based metabolomics analysis and histopathological inspection. The biochemical indexes of MDA, SOD, GSH, NO and XOD were measured. Gastrodia elata Blume could apparently ameliorate the damaged gastric glands and the biochemical parameters, enhance gastric acid secretion, and significantly relieve the inflammation of the stomach. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles and correlation network analysis revealed that Gastrodia elata Blume could effectively treat CAG via regulating energy and purine metabolisms, and by anti-oxidation and anti-inflammation effects.

Hepatotoxicity and hepatoprotection of Polygonum multiflorum Thund. as two sides of the same biological coin.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thund., a well-known and commonly-used TCM (Traditional Chinese Medicine) for treating hypertension, hyperlipidemia, premature graying of hair, and etc., has aroused wide concern for its reported potential liver toxicity. Due to its various active ingredients, the mechanisms underlying the hepatotoxicity of raw Polygonum multiflorum Thund (RPM) remain largely unknown. AIM OF THE STUDY: 1H NMR metabolomics was used to study the mechanism of RPM induced hepatotoxicity and disclosed the existence of hepatotoxicity and hepatoprotection conversion during RPM administration in mice. MATERIALS AND METHODS: Three dosages of RPM were administered by gavage to mice for consecutive 28 days. The serum and liver samples were collected and then subjected for histopathology observation, biochemical measurement and 1H NMR metabolic profiling. RESULTS: RPM caused oxidative stress and mitochondria dysfunction in mice, resulting in significant disturbance in energy metabolism, amino acid metabolism and pyrimidine metabolism and also inducing inflammatory responses. RPM induced hepatotoxicity in an apparent non-linear manner: the most severe in low dosage group, and to a less extent in medium group according to metabolomics analysis. The attenuation of liver injury in mice livers might result from the therapeutic effects, such as anti-oxidative capacity of RPM components. CONCLUSION: RPM exerted a complicated non-linear manner in healthy recipients, switching between hepatoxicity and hepatoprotection dependent on the dosage and status of the body.