Bioinspired ginsenoside Rg3 PLGA nanoparticles coated with tumor-derived microvesicles to improve chemotherapy efficacy and alleviate toxicity.

Breast cancer, a pervasive malignancy affecting women, demands a diverse treatment approach including chemotherapy, radiotherapy, and surgical interventions. However, the effectiveness of doxorubicin (DOX), a cornerstone in breast cancer therapy, is limited when used as a monotherapy, and concerns about cardiotoxicity persist. Ginsenoside Rg3, a classic compound of traditional Chinese medicine found in Panax ginseng C. A. Mey., possesses diverse pharmacological properties, including cardiovascular protection, immune modulation, and anticancer effects. Ginsenoside Rg3 is considered a promising candidate for enhancing cancer treatment when combined with chemotherapy agents. Nevertheless, the intrinsic challenges of Rg3, such as its poor water solubility and low oral bioavailability, necessitate innovative solutions. Herein, we developed Rg3-PLGA@TMVs by encapsulating Rg3 within PLGA nanoparticles (Rg3-PLGA) and coating them with membranes derived from tumor cell-derived microvesicles (TMVs). Rg3-PLGA@TMVs displayed an array of favorable advantages, including controlled release, prolonged storage stability, high drug loading efficiency and a remarkable ability to activate dendritic cells in vitro. This activation is evident through the augmentation of CD86+CD80+ dendritic cells, along with a reduction in phagocytic activity and acid phosphatase levels. When combined with DOX, the synergistic effect of Rg3-PLGA@TMVs significantly inhibits 4T1 tumor growth and fosters the development of antitumor immunity in tumor-bearing mice. Most notably, this delivery system effectively mitigates the toxic side effects of DOX, particularly those affecting the heart. Overall, Rg3-PLGA@TMVs provide a novel strategy to enhance the efficacy of DOX while simultaneously mitigating its associated toxicities and demonstrate promising potential for the combined chemo-immunotherapy of breast cancer.

Progress of cell membrane-derived biomimetic nanovesicles for cancer phototherapy.

In recent years, considerable attention has been given to phototherapy, including photothermal and photodynamic therapy to kill tumor cells by producing heat or reactive oxygen species (ROS). It has the high merits of noninvasiveness and limited drug resistance. To fully utilize this therapy, an extraordinary nanovehicle is required to target phototherapeutic agents in the tumor cells. Nanovesicles embody an ideal strategy for drug delivery applications. Cell membrane-derived biomimetic nanovesicles represent a developing type of nanocarrier. Combining this technique with cancer phototherapy could enable a novel strategy. Herein, efforts are made to describe a comprehensive overview of cell membrane-derived biomimetic nanovesicles for cancer phototherapy. The description in this review is mainly based on representative examples of exosome-derived biomimetic nanomedicine research, ranging from their comparison with traditional nanocarriers to extensive applications in cancer phototherapy. Additionally, the challenges and future prospectives for translating these for clinical application are discussed.

Efficacy and Mechanism of Active Fractions in Fruit of Amomum villosum Lour. for Gastric Cancer.

Amomi Fructus is the dried ripe fruit of Amomum villosum Lour. (A. villosum). It is a well-known traditional Chinese medicine widely used to treat gastrointestinal diseases, while the efficacy or mechanism of main components in Amomi Fructus on cancer treatment remains unknown. In this study, volatile oil of A. villosum (VOAV), total flavonoids of A. villosum (FNAV) and the other residue of A. villosum (RFAV) were distilled, extracted and separated as different active fractions of A. villosum. The cell toxicity test results indicated that VOAV and FNAV can effectively inhibit the cell growth of MFC cells. Flow cytometry test results confirmed that MFC cells were caused apoptosis after being treated with VOAV, FNAV or RFAV. VOAV, FNAV or RFAV induced MFC cells apoptosis through reactive oxygen species (ROS)-mediated mitochondrial pathway, evident by the increase of endogenous ROS and mitochondrial membrane potential collapse. In addition, FNAV exhibited robust inhibitory effects on MFC tumor growth, and could improve the health status of mice compared to that of mice in 5-FU treated group. To sum up, all the above results suggest that FNAV may be a good candidate for the development of new drugs for the treatment of gastric cancer.

Autologous erythrocytes delivery of berberine hydrochloride with long-acting effect for hypolipidemia treatment.

Discovery of novel pharmacological effects of berberine hydrochloride (BH) has made its clinical application valuable. However, further development and applications of BH are hampered by its short half-life and the side effects associated with its intravenous (iv) injection. To improve the hypolipidemia efficacy and reduce side effects, we encapsulated BH into biocompatible red blood cells (RBCs) to explore its sustained-release effect by hypotonic pre-swelling method. From in vitro evaluation, BH loaded RBCs (BH-RBCs) presented similar morphology and osmotic fragility to native RBCs (NRBCs). After the loading process, the BH-RBCs maintained around 69% of Na+/K+-ATPase activity of NRBCs and phosphatidylserine externalization value of BH-RBCs was about 26.1 ± 2.9%. The survival test showed that the loaded cells could circulate in plasma for over 9 d. For in vivo evaluation, a series of tests including pharmacokinetics study and hypolipidemic effect were carried out to examine the long-acting effect of BH-RBCs. The results showed that the release of BH in the loaded cells could last for about 5 d and the hypolipidemic effect can still be observed on 5 d after injection. BH-loaded autologous erythrocytes seem to be a promising sustained releasing delivery system with long hypolipidemic effect.

Metabolomics combined with pattern recognition and bioinformatics analysis methods for the development of pharmacodynamic biomarkers on liver fibrosis.

The major obstacle for the development of targeted therapies is the lack of pharmacodynamic (PD) biomarkers to provide an early readout of biological activities. As the modulation of metabolites may reflect the biological changes occurring in the targets, metabolomics is promising to be an efficient way to explore PD biomarkers. In the present study, a liver fibrosis rat model was established by intraperitoneal injection of CCl4 twice weekly for 6 weeks, the treatment of total aglycone extracts of Scutellaria baicalensis (TAES) was begun 4 weeks after the modeling, and gas chromatography-mass spectrometry (GC-MS) based metabolomics combined with pattern recognition and network analysis were carried out for the research on PD biomarkers of TAES on liver fibrosis. After 2 weeks of treatment, TAES shows positive effects on CCl4-induced liver fibrosis. In the metabolomics study, 63 urinary metabolites contributing to liver fibrosis were identified. Six metabolic pathways significantly enriched in metabolomics data were mapped onto a network to determine global patterns of metabolic alterations in liver fibrosis. By topological analysis, 6 metabolites with high centrality in the metabolic sub-network were selected as potential PD biomarkers. Within 24 h of the final administration, the 6 identified urine metabolic biomarkers with response to time variation of TAES were validated as PD biomarkers. This integrative study presents an attractive strategy to explore PD biomarkers, which may give insight into the actual pharmacological effect of target drugs, and the information from PD biomarkers can be combined with pharmacokinetics to select the optimal dose and a schedule of administration for the drugs.

Di-Huang-Yi-Zhi herbal formula attenuates amyloid-ß-induced neurotoxicity in PC12 cells.

Traditional Chinese medicine can be used for Alzheimer's disease management, such as the modern herbal formula Di-Huang-Yi-Zhi (DHYZ). In the present study, neuronal differentiated PC12 cells were used as a model to evaluate the effects of DHYZ against amyloid-ß peptide 25-35 (Aß25-35) induced neurotoxicity, particularly regarding cell proliferation, apoptosis and related events. Following treatment with DHYZ, cell viability, cell membrane damage, apoptosis, mitochondrial membrane potential, cytochrome c release, caspase-3 activity and levels of reactive oxygen species in PC12 cells were detected. The results demonstrated that pretreatment with DHYZ significantly protected PC12 cells from Aß25-35-induced proliferation inhibition, lactate dehydrogenase release and apoptosis, as well as upregulating mitochondrial membrane potential and downregulating cytochrome c release and caspase-3 activation. DHYZ also inhibited the Aß25-35-induced reactive oxygen species generation in PC12 cells. These observations suggest that DHYZ protected PC12 cells from the Aß-induced neurotoxicity.

Global and Targeted Metabolomics Evidence of the Protective Effect of Chinese Patent Medicine Jinkui Shenqi Pill on Adrenal Insufficiency after Acute Glucocorticoid Withdrawal in Rats.

Glucocorticoids are commonly used in anti-inflammatory and immunomodulatory therapies, but glucocorticoid withdrawal can result in life-threatening risk of adrenal insufficiency. Chinese patented pharmaceutical product Jinkui Shenqi pill (JKSQ) has potent efficacy on clinical adrenal insufficiency resulting from glucocorticoid withdrawal. However, the underlying molecular mechanism remains unclear. We used an animal model to study JKSQ-induced metabolic changes under adrenal insufficiency and healthy conditions. Sprague-Dawley rats were treated with hydrocortisone for 7 days with or without 15 days of JKSQ pretreatment. Sera were collected after 72 h hydrocortisone withdrawal and used for global and free fatty acids (FFAs)-targeted metabolomics analyses using gas chromatography/time-of-flight mass spectrometry and ultraperformance liquid chromatography/quadruple time-of-flight mass spectrometry. Rats without hydrocortisone treatment were used as controls. JKSQ pretreatment normalized the significant changes of 13 serum metabolites in hydrocortisone-withdrawal rats, involving carbohydrates, lipids, and amino acids. The most prominent effect of JKSQ was on the changes of FFAs and some [product FFA]/[precursor FFA] ratios, which represent estimated desaturase and elongase activities. The opposite metabolic responses of JKSQ in adrenal insufficiency rats and normal rats highlighted the "Bian Zheng Lun Zhi" (treatment based on ZHENG differentiation) guideline of TCM and suggested that altered fatty acid metabolism was associated with adrenal insufficiency after glucocorticoid withdrawal and the protective effects of JKSQ.

Metabolomics study of renal fibrosis and intervention effects of total aglycone extracts of Scutellaria baicalensis in unilateral ureteral obstruction rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellariae Radix (Scutellaria baicalensis Georgi) is a well-known Traditional Chinese Medicine (TCM) which mainly contains flavonoids. Our previous studies have demonstrated that total aglycone extracts of Scutellaria baicalensis (TAES) can improve kidney disease in rats. AIM OF THE STUDY: To investigate the renal fibrosis (RF) pathogenesis and TAES treatment mechanism in unilateral ureteral obstruction (UUO) rats, using a metabolomics approach based on gas chromatography-mass spectrometry (GC/MS). METHODS: Rats with RF were divided into 6 groups with rats subjected to sham operation as normal control. The effects of TAES on some RF closely related parameters in UUO rats were investigated. A metabolomics method, based on GC/MS, was developed to monitor metabolic alterations in urine. Multivariate data analysis was utilized to identify biomarkers potentially associated with RF and the anti-RF activity of TAES. Ontology-based enrichment analysis by BiNChE and pathway analysis by MetPA aid in the interpretation of difference metabolites. RESULTS: After 10 days of treatment, the parameters of renal function begin returning to normal, and the abnormal high expressions of genes associated with extracellular matrix (ECM) were relived. In the metabolomics study, metabolic perturbations induced by UUO were reversed after treatment and TAES showed a dose-dependent therapy effect on RF, meanwhile, 18 potential biomarkers associated with RF were identified. Enrichment analysis of metabolites shows an over representation of mostly alkane-alpha, omega-diamine and alpha, omega-dicarboxylic acid, and these biomarkers are primarily involved in Glycine, serine and threonine metabolism, Retinol metabolism, Arginine and proline metabolism and Fructose and mannose metabolism. CONCLUSIONS: Our findings indicate that TAES have positive effects on UUO-induced RF in rats, meanwhile, metabolomics method coupled with metabolites enrichment analysis is a useful tool for revealing the pathogenesis of diseases and action mechanism of TCM on the whole body.

Urinary metabolomic strategy to evaluate Compound Danshen Dripping Pills for myocardial ischaemia in rats.

Compound Danshen Dripping Pill (CDDP) has been used for the treatment of coronary heart disease for decades. We aimed to increase the understanding of the mechanisms by evaluating the urinary metabolomics of CDDP using Gas Chromatography-Mass Spectrometer (GC-MS) in a myocardial ischaemia (MI) rat model. One hundred Sprague-Dawley rats were divided into Con (normal saline and no surgery), Con+ (107 mg/kg d CDDP solution and no surgery), Sham (normal saline and surgery without aorta ligation), Mod (normal saline and surgery with aorta ligation), and Mod+ (107 mg/kg d CDDP solution and surgery with aorta ligation) groups. Urine samples on days 0, 3, 14, and 28 were tested using GC-MS and analyzed with PCA and partial least squares-discriminant analysis models. In the Mod group, creatine kinase and malondialdehyde levels were higher, and superoxide-dismutase levels were lower; the same variables normalized in the Mod+ group. CDDP resulted in improvement in the Mod+ group, as indicated by the reduced necrosis in the myocardial tissue. A total of 36 metabolites were identified in the urine samples, and 8 metabolites (malate, succinate, creatinine, methionine, cysteine, serine, phenylalanine, and tyrosine) were increased remarkably and recovered to normal levels after treatment with CDDP. Differentially expressed metabolites implied that energy, amino acid, fatty acid, and polyol metabolism might be disrupted by MI and reversed by CDDP. Urinary metabolomics provide a dynamic monitoring approach that highlights interference by MI and the therapeutic effects of CDDP on MI in rats throughout the recovery process.

Acorus tatarinowii Schott extract protects PC12 cells from amyloid-beta induced neurotoxicity.

Amyloid-beta induced neurotoxicity has been identified as a major cause of Alzheimer's disease. Acorus tatarinowii Schott is one of the most frequently used Chinese herbs for Alzheimer's disease treatment. However, the effects of Acorus tatarinowii Schott on amyloid-beta mediated nerve cell damage remains unknown. In the present study, neuronal differentiated PC12 cells were used as a model to evaluate the effects of A. tatarinowii Schott extract (ATSE) against Abeta25-35 induced neurotoxicity. The results showed pretreatment with ATSE significantly protected PC12 cells from Abeta25-35 induced cell death, lactate dehydrogenase release, DNA damage, mitochondrial dysfunction and cytochrome c release from mitochondria. In addition, pretreatment with ATSE also significantly inhibited Abeta25-35 induced caspase-3 activation and reactive oxygen species generation in PC12 cells. These observations suggested that ATSE protects PC12 cells from amyloid-beta induced neurotoxicity.

The in vivo and in vitro study of polysaccharides from a two-herb formula on ulcerative colitis and potential mechanism of action.

ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum and Astragalus membranaceus are two traditional medicinal herbs widely used in China for nourishing Yin and reinforcing Qi. The purpose of the study was to investigate the prophylactic and curative effects of crude polysaccharides (QHPS) extracted from a two-herb formula composed of Lycium barbarum and Astragalus membranaceus at a ratio of 2:3 in colitis rats, and to further elucidate the potential mechanism of action in epithelial cell proliferation in vitro. MATERIALS AND METHODS: An acetic acid (AA)-induced ulcerative colitis rat model was applied in the study. Two independent protocols were used to assess the prophylactic and curative effects of QHPS, respectively, in which rats were either pre-treated with QHPS (0.18g/kg) for 14 days prior to AA induction, or post-treated with QHPS for 7 days after AA induction. The stool consistency and weight loss were used to evaluate disease activity. The morphological changes in intestinal mucosa at the end of the experiments were observed. The serum levels of endotoxin (EDT), diamine oxidase (DAO) and d-lactate (DLA), important biochemical markers for evaluating intestinal mucosal structure and function, were measured. In the in vitro mechanistic studies, rat intestinal epithelial cells (IEC-6) were used to access for epithelium regeneration. RESULTS: The intra-colonic instillation of AA induced ulcerative colitis in rat, as indicated by diarrhea, weight loss, and colonic mucosal damage. Both prophylactic and curative treatments effectively reduced the weight loss and diarrhea and attenuated the colonic mucosal damage associated with inducible colitis. The significant increase in serum levels of DAO, DLA and EDT was induced by AA and inhibited by QHPS treatment. Moreover, QHPS could significantly stimulate IEC-6 proliferation in a dose-dependent manner (p<0.05). CONCLUSION: The present study indicated for the first time that polysaccharides extracted from this two-herb formula can protect against experimental ulcerative colitis, presumably by promoting the recovery of the intestinal barrier.

Metabolic Signatures of Kidney Yang Deficiency Syndrome and Protective Effects of Two Herbal Extracts in Rats Using GC/TOF MS.

Kidney Yang Deficiency Syndrome (KDS-Yang), a typical condition in Chinese medicine, shares similar clinical signs of the glucocorticoid withdrawal syndrome. To date, the underlying mechanism of KDS-Yang has been remained unclear, especially at the metabolic level. In this study, we report a metabolomic profiling study on a classical model of KDS-Yang in rats induced by hydrocortisone injection to characterize the metabolic transformation using gas chromatography/time-of-flight mass spectrometry. WKY1, a polysaccharide extract from Astragalus membranaceus and Lycium barbarum, and WKY2, an aqueous extract from a similar formula containing Astragalus membranaceus, Lycium barbarum, Morinda officinalis, Taraxacum mongolicum, and Cinnamomum cassia presl, were used separately for protective treatments of KDS-Yang. The changes of serum metabolic profiles indicated that significant alterations of key metabolic pathways in response to abrupt hydrocortisone perturbation, including decreased energy metabolism (lactic acid, acetylcarnitine), lipid metabolism (free fatty acids, 1-monolinoleoylglycerol, and cholesterol), gut microbiota metabolism (indole-3-propionic acid), biosynthesis of catecholamine (norepinephrine), and elevated alanine metabolism, were attenuated or normalized with different degrees by the pretreatment of WKY1 or WKY2, which is consistent with the observations in which the two herbal agents could ameliorate biochemical markers of serum cortisone, adrenocorticotropic (ACTH), and urine 17-hydroxycorticosteroids (17-OHCS).

Current understanding on antihepatocarcinoma effects of xiao chai hu tang and its constituents.

Xiao Chai Hu Tang (XCHT), a compound formula originally recorded in an ancient Chinese medical book Shanghanlun, has been used to treat chronic liver diseases for a long period of time in China. Although extensive studies have been demonstrated the efficacy of this formula to treat chronic hepatitis, hepatic fibrosis, and hepatocarcinoma, how it works against these diseases still awaits full understanding. Here, we firstly present an overview arranging from the entire formula to mechanism studies of single herb in XCHT and their active components, from a new perspective of "separation study," and we tried our best to both detailedly and systematically organize the antihepatocarcinoma effects of it, hoping that the review will facilitate the strive on elucidating how XCHT elicits its antihepatocarcinoma role.

Metabonomic strategy to the evaluation of chinese medicine compound danshen dripping pills interfering myocardial ischemia in rats.

Coronary heart disease (CHD) is one of the highest mortality diseases in the world. Traditional Chinese medicine compound Danshen dripping pills (CDDPs) have currently made a great achievement in treating CHD. However, the therapeutic mechanism of CDDP is often poorly interpreted. In this study, a GC-MS-based metabonomic study was conducted to assess the holistic efficacy of CDDP for myocardial infarction in male Sprague-Dawley rats, which were divided into the control group, the sham group, the model group, the control + CDDP group, and the model + CDDP, with CDDP at a dose of 107 mg/kg·d (equal to 1.8 mL/kg·d). The metabonomic findings demonstrated great differences of metabolic pattern among sham, model, and the model + CDDP in the orthogonal partial least squares discriminant analysis (OPLS-DA) models, which coordinated well with the assessment of plasma biochemistry and histopathological assay. Differentially expressed metabolites suggested that energy metabolism, glycolysis, and lipid metabolism might be disrupted by myocardial infarction. Both the potential metabolic biomarkers and the biochemical histopathological indices were regulated effectively by CDDP.

Metabolic fate of tea polyphenols in humans.

Polyphenols, a ubiquitous group of secondary plant metabolites sharing at least one aromatic ring structure with one or more hydroxyl groups, represent a large group of natural antioxidants abundant in fruits, vegetables, and beverages, such as grape juice, wine, and tea, and are widely considered to contribute to health benefits in humans. However, little is yet known concerning their bioactive forms in vivo and the mechanisms by which they may alter our metabolome, which ultimately contribute toward disease prevention. Here we report a study to determine the metabolic fate of polyphenolic components in a Chinese tea (Pu-erh) in human subjects using a metabonomic profiling approach coupled with multivariate and univariate statistical analysis. Urine samples were collected at 0 h, 1 h, 3 h, 6 h, 9 h, 12 h, and 24 h within the first 24 h and once a day during a 6 week period including a 2 week baseline phase, a 2 week daily Pu-erh tea ingestion phase, and a 2 week "wash-out" phase, and they were analyzed by gas chromatography mass spectrometry and liquid chromatography mass spectrometry. The dynamic concentration profile of bioavailable plant molecules (due to in vivo absorption and the hepatic and gut bacterial metabolism) and the human metabolic response profile were measured and correlated with each other. This study demonstrates that the metabonomic strategy will enable us to integrate the overwhelming amount of metabolic end points as a systems' response to the absorption, metabolism, and disposition of a multicomponent botanical intervention system, leading to a direct elucidation of their mechanisms of action.

Differentiation of Schisandra chinensis and Schisandra sphenanthera using metabolite profiles based on UPLC-MS and GC-MS.

Historically, Schisandra chinensis and S. sphenanthera have been widely used in traditional Chinese medicine. Although both species are in the genus Schisandra, they have dissimilar therapeutic effects that may be attributed to compositional differences in secondary metabolites. We developed a method to compare these metabolites obtained from the above plant species using ultra-performance liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry coupled with multivariate statistical analyses. The critical markers we used to discriminate between both plant species resulted in the identification and quantification of six lignans and seven essential oils. We believe that our approach provided a sensitive, reliable and robust method to conveniently classify medicinal plants that can be used to explore subtle variations among different species or plants from different geographical locations.

[Determination of salylic acid, syringic acid, benzoic acid and anthranilic acid in Radix Isatidis by HPCE].

OBJECTIVE: To develop a simple and rapid capillary electrophoresis (CE) method for the separation and determination of four active organic acids including salicylic acid, syringic acid, benzoic acid, and anthranilic acid in Radix Isatidis. METHOD: The HPCE system consisted of a fused-silica capillary column of 47.3 cm (38.3 cm to the detector) x50 microm i.d. and a mixture ofacetonitrile-borate buffer (15% acetonitrile, 25 mmol L(-1) borate, 15 mmol L(-1) beta-CD, pH 9.10) solution as the operating buffer. The applied voltage was 11.5 kV and the UV detection was set at 220 nm. The effects of the applied voltage, detection wavelength, and the pH of buffer, the concentration of buffer, acetonitrile and beta-CD were investigated. RESULT: The linear calibration rang was 3.0-90 mg L(-1) (r=0.9994) for salylic acid, 4.0-120 mg L(-1) (r=0.9995) for syringic acid, 2.0-60 mg L(-1) (r=0.9998) for benzoic acid and 5.0-100 mg L(-1) (r=0.9992) for anthranilic acid. The recoveries of salylic acid, syringic acid, benzoic acid and anthranilic acid were 95.9%-102.6%, 98.6%-103.4%, 98.7%-104.1%, 96.1%-104.3% respectively. The detection limits of salylic acid, syringic acid, benzoic acid and anthranilic acid were 0.7, 1.1, 1.2 and 1.5 mg L(-1), respectively.

Characterization of pu-erh tea using chemical and metabolic profiling approaches.

In this study, the chemical constituents of pu-erh tea, black tea, and green tea, as well as those of pu-erh tea products of different ages, were analyzed and compared using a chemical profiling approach. Differences in tea processing resulted in differences in the chemical constituents and the color of tea infusions. Human biological responses to pu-erh tea ingestion were also studied by using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) in conjunction with multivariate statistical techniques. Metabolic alterations during and after pu-erh tea ingestion were characterized by increased urinary excretion of 5-hydroxytryptophan, inositol, and 4-methoxyphenylacetic acid, along with reduced excretion of 3-chlorotyrosine and creatinine. This study highlights the potential for metabonomic technology to assess nutritional interventions and is an important step toward a full understanding of pu-erh tea and its influence on human metabolism.

Ultra-performance LC/TOF MS analysis of medicinal Panax herbs for metabolomic research.

In this study, metabolite profiling of five medicinal Panax herbs including Panax ginseng (Chinese ginseng), Panax notoginseng (Sanchi), Panax japonicus (Rhizoma Panacis Majoris), Panax quinquefolium L. (American ginseng), and P. ginseng (Korean ginseng) were performed using ultra-performance LC-quadrupole TOF MS (UPLC-QTOFMS) and multivariate statistical analysis technique. Principal component analysis (PCA) of the analytical data showed that the five Panax herbs could be separated into five different groups of phytochemicals. The chemical markers such as ginsenoside Rf, 20(S)-pseudoginsenoside F11, malonyl gisenoside Rb1, and gisenoside Rb2 accountable for such variations were identified through the loadings plot of PCA, and were identified tentatively by the accurate mass of TOFMS and partially verified by the available reference standards. Results from this study indicate that the proposed method is reliable for the rapid analysis of a group of metabolites present in herbal medicines and other natural products and applicable in the differentiation of complex samples that share similar chemical ingredients.

Pharmacometabonomic phenotyping reveals different responses to xenobiotic intervention in rats.

In conventional pharmacological studies, intersubject differences within an animal strain are normally neglected, leading to variations in pharmacological outcomes in response to the same stimulus. Using two classical experimental models, the Streptozotocin (STZ)-induced diabetic model of Wistar rats and the high-energy, diet-induced obesity model of Sprague-Dawley rats, we demonstrate that the different outcomes of STZ or diet intervention are closely associated with variation in predose (baseline) urinary metabolic profiles of the rats. The pharmacometabonomic analysis of predose metabolic profiles indicates that the intersubject difference is, to a great extent, associated with gut-microbiota, which predisposes different pathophysiological outcomes upon diet alteration or chemical stimulus. We hypothesize that there may exist an important association between observations from these two models and the obese/diabetic human population in that subtle variations in metabolic phenotype may predetermine different systems' responses to xenobiotic perturbation, ultimately leading to varied pathophysiological processes. Results from two independent models also suggest that the pharmacometabonomics approach is of great importance in the study of pharmacology and clinical drug evaluations, where endogenous metabolite signatures of predose individuals should be taken into consideration to minimize intersubject difference and the resulting variation in the postdose pharmacological outcomes.