Exploring the Constituents and Mechanisms of Polygonum multiflorum Thunb. in Mitigating Ischemic Stroke: A Network Pharmacology and Molecular Docking Study.

Polygonum multiflorum Thunb. (PMT) has shown promise in exerting cerebrovascular protective effects, and its potential for treating ischemic stroke (IS) has garnered attention. However, the lack of clarity regarding its chemical constituents and mechanisms has significantly hindered its clinical application. In this study, we employed network pharmacology and molecular docking techniques for the first time to elucidate the potential compounds and targets of PMT in treating IS. The databases CTD, DrugBank, DisGeNET, GeneCards, OMIM, TTD, PGKB, NCBI, TCMIP, CNKI, PubMed, ZINC, STITCH, BATMAN, ETCM and Swiss provided information on targets related to IS and components of PMT, along with their associated targets. We constructed "compound-target" and protein-protein interaction (PPI) networks sourced from the STRING database using the Cytoscape software. Gene Ontology (GO) enrichment analysis and KEGG pathway analysis were conducted using the DAVID database. Molecular docking between core targets and active compounds was conducted using Autodock4 software. Experiments were performed in an oxygen-glucose deprivation and reperfusion (OGD/R) model to validate the anti-IS activity of compounds isolated from PMT preliminarily. Network pharmacological analysis revealed 16 core compounds, including resveratrol, polydatin, TSG, ω- hydroxyemodin, emodin anthrone, tricin, moupinamide, and others, along with 11 high-degree targets, such as PTGS1, PTGS2, ADORA1, ADORA2, CA1, EGFR, ESR1, ESR2, SRC, MMP3 and MMP9. GO and KEGG enrichment analyses revealed the involvement of HIF-1, Akt signaling pathway and energy metabolism-related signaling pathways. Molecular docking results emphasized eight key compounds and confirmed their interactions with corresponding targets. In vitro OGD/R model experiments identified TSG and tricin as the primary active substances within PMT for its anti-stroke activity. This study contributes new insights into the potential development of PMT for stroke prevention and treatment.

High efficient preparation of low molecular weight galactomannan from Leucaena leucocephala galactomannan through the combination of hydrogen peroxide and oxalic acid.

Researchers have always been interested in polysaccharide degradation because of the increased biological activity and usability following degradation. In this work, low molecular weight galactomannan (LMW-GM) was produced through the degradation of galactomannan by H2O2 and oxalic acid (OA). The optimal reaction conditions were found by conducting the response surface optimization experiment based on single-factor experiment and kinetics analysis. Under these conditions, the LMW-GM yield was 69.48 ± 1.02 %. Ultimately, an analysis of the degradation process revealed that OA attacked GM indiscriminately, and H2O2 has a stronger effect on the removal of branched chains while degrading GM. Hence, the degradation steps were rearranged as H2O2 was added 20 min before OA at a constant total time. The LMW-GM yield was successfully increased to 76.49 ± 1.27 %. The goal of this work is hopefully to give a theoretical foundation for the low-cost preparation and industrial production of the degradation of galactomannan.

p-Toluenesulfonic acid enhanced neutral deep eutectic solvent pretreatment of soybean straw for efficient lignin removal and enzymatic hydrolysis.

Deep eutectic solvent (DES) is a newly-emerged green solvent for efficient pretreatment of lignocellulosic feedstock. To improve the component fractionation performance of neutral DES, p-toluenesulfonic acid (p-TsOH) was employed as catalyst to form a novel ternary DES with benzyltriethylammonium chloride (TEBAC) and glycerol (Gly) for pretreatment of soybean straw. Under the optimum reaction conditions (TEBAC:Gly = 1:12, 1.6 wt% p-TsOH and reacted at 90 °C for 160 min), the lignin and hemicellulose removal from soybean straw were amounted to 92.0 % and 88.2 %, respectively. The pretreated substrate showed satisfactory enzymatic hydrolysis performance, as the glucose and reducing sugar concentrations reached 37.3 g/L and 42.3 g/L, respectively, after 72 h saccharification under the action of cellulase with a relatively low enzyme loading of 10 FPU/g cellulose.This method provides an efficient and mild route for utilization of agricultural waste and production of platform monosaccharides.

Modified Podophyllotoxin Phenoxyacetamide Phenylacetate Derivatives: Tubulin/AKT1 Dual-Targeting and Potential Anticancer Agents for Human NSCLC.

Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 µM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 µM) and 300 times higher than gefitinib (IC50 = 32.15 µM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.

1H NMR Spectroscopy-Based Metabolomics Approach to Study the Anti-Stroke Activity of G-3702, a Novel Better Alternative to DL-3-n-Butylphthalide.

Cerebrovascular disease is the leading cause of disability and death, and ischemic stroke accounts for most stroke cases. However, few effective drugs are available for the treatment of ischemic stroke; thus, there is an urgent need to develop effective drugs to treat ischemic stroke. DL-3-n-butylphthalide (NBP) is clinically approved as an anti-ischemic drug in China, but its potential hepatotoxicity limits its use. G-3702 (a structural analogue of NBP) is synthesized with the boron hydroxyl group replacing carbonyl group. G-3702 significantly enhanced the survival of middle cerebral artery occlusion (MCAO) rats, decreased neurobehavioral deficit scores and cerebral infarct volume, comparable with NBP, which was also supported by tissue damage assessment, immunohistochemistry staining, biochemical parameters and ELISA assay. G-3702 showed better anti-stroke activity than NBP according to 1H NMR spectroscopy-based metabolomics analysis, demonstrating the feasibility of metabolomics approach to assess drug efficacy. G-3702 markedly ameliorated energy metabolism, attenuated oxidative and inflammatory stress during ischemia/reperfusion (I/R). G-3702 exhibited good neuroprotective effects against I/R induced injury and favorable little possibility of hepatotoxicity, which made it a promising anti-stroke drug and better NBP alternative.

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.

NMR-based metabolomics approach to evaluate the toxicological risks of Tibetan medicine 'Ershiwuwei Shanhu' pill in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: 'Ershiwuwei Shanhu' Pill (ESP) is a classic Tibetan medicine to treat neurological disorders in nervous system, especially for neurological pains and epilepsy. It contains many Tibet-specific mineral medicines, among which Halloysite (Halloysitum rubrum, HR) was regarded as the main active one. As mineral medicines contain heavy metals with poor solubility, the doubts about its safety restricted its clinical application and further development. AIM OF THE STUDY: A 7-day acute toxicity of ESP and its main active mineral medicine HR was systematically studied for investigating the safety of ESP and exploring the role of HR in ESP's potential toxicity. MATERIALS AND METHODS: In this study, the acute oral toxicity assessment of formula-ESP and HR were performed on rats for 7 days at doses equivalent to 10 (1 g/kg) and 40 times (4 g/kg) the typical clinical dose (0.1 g/kg). 1H NMR based metabolomics profiling, aided with biochemical analysis and histopathology, was conducted to explore the global metabolic changes in the livers and kidneys of the administrated rats. RESULTS: High-dose HR caused oxidative stress, energy metabolism disorders, purine metabolism impairments and amino acid metabolism imbalance in rats, resulting in hepatotoxicity and nephrotoxicity, which in accordance with the increased biochemical index in blood (ALT, AST, BUN and CRE). ESP (low-dose) induced metabolites changes were far more less than HR in livers, showcasing the distinct advantage of formula in reducing toxicity. Furthermore, low-dose ESP disturbed renal metabolism in a way similar to high-dose HR, which implies that HR might be the major source of the potential nephrotoxicity of ESP. CONCLUSION: HR exhibited potential hepatoxicity and nephrotoxicity, but the formula- 'Ershiwuwei Shanhu' Pill which contains HR is considered relatively safe.

Hepatotoxicity or hepatoprotection of emodin? Two sides of the same coin by 1H-NMR metabolomics profiling.

Emodin is the major anthraquinone component of many important traditional Chinese herbs, such as Rheum palmatum L. and Polygonum multiflorum Thunb. They have been popular health products but recently aroused concerns about their hepatotoxicity, which are believed to be arising from the contained anthraquinones, such as emodin. However, emodin exerts potent hepatoprotective ability, such as anti-fibrotic, anti-oxidative, and anti-inflammatory effects. In this study, 1H NMR based metabolomics approach, complemented with histopathological observation, biochemical measurements, western blotting analysis and real-time quantitative PCR (RT-qPCR), was applied to interpret the paradox of emodin (30 mg/kg, 10 mg/kg BW) using both healthy mice (male, ICR) and chronic CCl4-injured mice (0.1 mL/kg, 0.35% CCl4, 3 times a week for a month). Emodin exerted a weight loss property associated with its lipid-lowing effects, which helped alleviate CCl4-induced steatosis. Emodin effectively ameliorated CCl4-induced oxidative stress and energy metabolism dysfunction in mice liver via regulating glucose, lipid and amino acid metabolism, and inhibited excessive inflammatory response. In healthy mice, emodin only exhibited hepatoxicity on high-dosage by disturbing hepatic anti-oxidant homeostasis, especially GSH and xanthine metabolism. This integrated metabolomics approach identified the bidirectional potential of emodin, which are important for its rational use.

Activation of Adenosine A1 Receptor in Ischemic Stroke: Neuroprotection by Tetrahydroxy Stilbene Glycoside as an Agonist.

Ischemic stroke is the main cause of death/disability, posing a great menace to human health. Though efforts to search for therapeutic drugs are ongoing, few of them have succeeded. Adenosine A1 receptor (A1R) activation could ameliorate ischemic injury, representing a very tempting target for stroke treatment. Tetrahydroxy stilbene glycoside (TSG), a potent antioxidant from the well-known Chinese herb Polygonum multiflorum Thunb., has been reported to have notable neuroprotective activities but the underlying mechanisms are elusive. This study investigated the mechanism of TSG focusing on A1R. TSG markedly decreased mortality, neurological deficit score, cerebral infarct size and brain water content of MCAO rats, and ameliorated the disorders in purine metabolism, energy metabolism and antioxidative defense system. TSG helped the survival of SH-SY5Y cells in OGD/R by alleviating oxidative stress and glutamate release, and by maintaining calcium homeostasis. TSG effects were abolished by A1R antagonist DPCPX. Docking and binding assays confirmed the binding of TSG with A1R. In addition, TSG upregulated the A1R level lowered by MCAO and OGD/R. The downstream signals of A1R activation, ERK1/2, HIF-1α and NF-κB contributed to the neuroprotection of TSG. Moreover, void of "well-known" cardiovascular side effects of classical A1R agonists, TSG showcased its great potential for stroke treatment.

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.

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.

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.

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.

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.

Hepatoprotection of Herpetospermum caudigerum Wall. against CCl4-induced liver fibrosis on rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Herpetospermum caudigerum Wall. (HCW) is a traditional Tibetan medicine, which has been used to ameliorate liver injuries in the folk. AIM OF THE STUDY: Liver fibrosis has been recognized as a major lesion of the liver that leads to liver cirrhosis/hepatocarcinoma and even to death in the end. This study aims to demonstrate the protective effect of HCW against CCl4-induced liver injury in rats and to explore the underlying mechanisms. MATERIALS AND METHODS: Hepatic fibrosis was induced by intraperitoneal injection of CCl4. Liver function markers, fibrosis markers, serum anti-oxidation enzymes as well as elements levels were determined. Serum and liver tissues were subjected to NMR-based metabolomics and multivariate statistical analysis. RESULTS: HCW could significantly reduce the elevated levels of fibrosis markers such as hyaluronidase, laminin, Type III procollagen and Type IV collagen in the serum, improve the activities of the antioxidant enzymes, and effectively reverse the abnormal levels of elements in liver fibrosis rats. Correlation network analysis revealed that HCW could treat liver fibrosis by ameliorating oxidative stress, repairing the impaired energy metabolisms and reversing the disturbed amino acids and nucleic acids metabolisms. CONCLUSION: This integrated metabolomics approach confirmed the validity of the traditional use of HCW in the treatment of liber fibrosis, providing new insights into the underlying mechanisms.

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.

Tibetan Medical Formula Shi-Wei-Gan-Ning-Pill Protects Against Carbon Tetrachloride-Induced Liver Fibrosis - An NMR-Based Metabolic Profiling.

Liver fibrosis is a severe health problem, threatening the life quality and causing death, raising great concerns worldwide. Shi-Wei-Gan-Ning-Pill (SWGNP) is a traditional Tibetan recipe used to treat hepatic injuries; however, its hepatoprotective mechanism has not yet fully clarified. In this study, histological staining, biochemical assays, and elements determination were applied to evaluate the anti-fibrotic efficacy of SWGNP on a carbon tetrachloride (CCl4) induced hepato-fibrosis rat model. NMR-based metabolomics combined with orthogonal partial least squares-discriminant analysis (OPLS-DA), canonical regression analysis, and correlation networks analysis was used to characterize the potential biomarkers as well as metabolic pathways associated with the hepatoprotective activity of SWGNP. The results showed that SWGNP could significantly attenuate the pathological changes and decrease the levels of fibrosis markers (ColIV, HA, LN, and PCIII), and regulate the disordered elements distribution. Multivariate analysis and correlation network analysis revealed that SWGNP could protect rats against CCl4-induced liver fibrosis through anti-oxidation, repairing the impaired energy metabolisms and reversing the disturbed amino acids and nucleic acids metabolisms. In conclusion, this integrated metabolomics approach provided new insights into the mechanism of the hepatoprotective effect of SWGNP in liver fibrosis disease.

Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach.

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.