The mechanism of Renshen-Fuzi herb pair for treating heart failure-Integrating a cardiovascular pharmacological assessment with serum metabolomics.

Background: Renshen-Fuzi herb pair (RS-FZ) is often used in the clinical treatment of heart failure (HF) and has a remarkable therapeutic effect. However, the mechanism of RS-FZ for treating HF remains unclear. In our study, we explored the mechanism of RS-FZ for treating HF. Methods: Evaluation of RS-FZ efficacy by cardiovascular pharmacology. Moreover, Global metabolomics profiling of the serum was detected by UPLC-QTOF/MS. Multivariate statistics analyzed the specific serum metabolites and corresponding metabolic pathways. Combining serum metabolomics with network pharmacology, animal experiments screened and validated the critical targets of RS-FZ intervention in HF. Results: RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (brain natriuretic peptide) level in rats with HF. Through topological analysis of the "Metabolite-Target-Component" interaction network, we found that 79 compounds of RS-FZ directly regulated the downstream specific serum metabolites by acting on four critical target proteins (CYP2D6, EPHX2, MAOB, and ENPP2). The immunohistochemistry results showed that RS-FZ observably improved the expression of CYP2D6 and ENPP2 proteins while decreasing the expression of EPHX2 and MAOB proteins dramatically. Conclusion: The integrated cardiovascular pharmacological assessment with serum metabolomics revealed that RS-FZ plays a crucial role in the treatment of HF by intervening in CYP2D6, EPHX2, MAOB, and ENPP2 target proteins. It provides a theoretical basis for RS-FZ for treating HF.

The Scientific Basis and Advantage of Human Experiential Assessment in the quality control of Chinese Herbal Medicines exampling as Schisandrae Chinensis Fructus.

Experiential quality assessment(EQA) is an important sensory analysis for judging herbal quality grades. Because of the high empirical utility of expert experience, the consistency, science and inheritance of such experience are continuously in dispute. To explore the scientific evidence for this subjective method, we designed a Delphi expert investigation coupled with chemical analysis to evaluate the quality of Schisandrae Chinensis Fructus (SCF). Initially, 13 experts were invited to independently evaluate the grades of 11 batches of SCF. After screening the consistency and repeatability of the evaluation results, typical samples of all quality levels were identified. Seven significant physical characters were detected; colour and size were found to be the key parameters for identifying SCF quality. Based on this correlation, a decision tree model was ultimately established and converted to a quality evaluation card. Over 80% consistency in a novice test demonstrated the technical advantages and application characteristics of the model. Further correlation analysis revealed that EQA quality grades of SCF were positively correlated to the content of polysaccharides and polyphenols, while negatively correlated to the content of lignans. Biological activities were also approving it. In summary, our study proves that subjective EQA is consistency, repeatability and could be inherited.

Quality Assessment of Panax notoginseng from Different Regions through the Analysis of Marker Chemicals, Biological Potency and Ecological Factors.

Panax notoginseng (Burk.) F.H. Chen, called Sanqi in China, is a perennial herb that has been used as a medicinal herb in traditional Chinese medicine for more than 400 years. Because notoginseng is included in many proprietary Chinese medicines, the quality of notoginseng directly affects its efficacy and safety. However, considering the complex and special growth environment requirements of notoginseng, it is insufficient to evaluate its quality based solely on the analysis of marker chemicals. Thus, in this study, we tried to evaluate the quality of notoginseng with integrated indicators: (1) the concentration of five marker chemicals, notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1 and ginsenoside Rd; (2) the anticoagulant activity (ACA); and (3) twenty-one ecological factors (e.g., longitude, latitude, elevation and soil data). Using these 27 parameters, notoginseng from different regions could be distinguished effectively, indicating a remarkable divergence of quality. A correlation analysis showed that variations of the ecological factors were closely associated with the saponins content and biopotency. For instance, the total nitrogen (TN), alkali hydrolysis nitrogen (AHN) and rapidly available potassium (RAPT) were significantly correlated with ACA, and RAPT was significantly correlated with the content of ginsenoside Rd and notoginsenoside R1. The results demonstrated that the high-quality notoginseng was produced from the emerging regions such as Kunming, Qujing and Honghe, which had higher ACA and saponin content than the notoginseng produced in traditional regions such as Wenshan and Baise.

[Precision medicine-oriented safety assessment strategy for traditional Chinese medicines: disease-syndrome-based toxicology].

Drug toxicity is commonly divided into intrinsic and idiosyncratic types. The former can be generally uncovered in the preclinical safety evaluation stage by conventional toxicological experiments, while the latter is usually found only in the clinical evaluation stage, which is the main cause of severe adverse reactions and withdrawal of post-marketing drugs. Assessment and prediction of idiosyncratic toxicity is a challenging problem worldwide, and is an essential in the development of translational toxicology and precision medicine. Since traditional Chinese medicines (TCMs) have been applied for thousands of years with long experience in clinical efficacy and safety, idiosyncratic toxicity is regarded as an important factor for traditional "non-toxic" medicines and is associated with multiple individual states including different diseases, syndromes, habitus, etc. However, these individual conditions related to disease are often difficult to be resolved in conventional toxicological experiments, leading to insufficient translation of the experimental results into clinical application. We took an approach of systematic analysis of the differences and similarities in toxic property, medication rule and evaluating requirement between TCMs and chemical synthetic medicines. We present a novel and clinic-associated safety assessment strategy, namely as "disease-syndrome-based toxicology", for TCMs. The strategy is able to access the relativity, susceptibility and controllability of the toxicity of TCMs. The new strategy provides a theoretical and methodological guidance to practice and development of the TCM in favor of precision medicine.

[Study on dosage-toxicity/efficacy relationship of prepared rhubarb on basis of symptom-based prescription theory].

OBJECTIVE: To investigate the dosage-efficacy/toxicity relationship of prepared rhubarb, in order to explore the bidirectional effects in hepatoprotection and hepatotoxicity of prepared rhubarb and the objective authenticity for attenuating toxicity by processing. METHOD: Normal and pathological animals were adopted simultaneous to investigate the effect of total extracts from prepared rhubarb within a high dose range (2.0, 5.4, 14.7, 40.0 g x kg(-1) x d(-1)) on normal state, biochemical index and histopathology of experimental animals. The factor analytic approach was used to analyze the dosage-efficacy/toxicity relationship of prepared rhubarb. RESULT: The factor analytic approach was used to extract two common factors from the nine biochemical indexes. The firs common factor was mainly dominated by HA, LN and TGF-ß1, and could be explained as fibrotic factors. The second common factor was mainly dominated by ALT, AST and ALP, and could be explained as cellular factor. The results of the factor analysis suggested that prepared rhubarb showed significant bidirectional effects in hepatoprotection and hepatotoxicity, which could protect liver in CC14 injured chronic hepatic injury, but had a certain hepatotoxic effect to normal animals. The pathological examination showed consistent results with the factor analysis. Under comparable dosages, prepared rhubarb showed a stronger liver protecting effect than crude rhubarb, with a lower toxicity. CONCLUSION: Although prepared rhubarb has a certain hepatotoxic effect to normal animals, it has also a significant therapeutic effect to animals with liver injury. The results proved the symptom-based prescription theory and the scientificity of the symptom-based medication. The symptom-based prescription theory is important to correctly realize the dosage-efficacy/toxicity relationship of traditional Chinese medicines and guide the symptom-based medication.

Needle-free injection of insulin powder: delivery efficiency and skin irritation assessment.

Insulin is widely used in treating diabetes, but still needs to be administered by needle injection. This study investigated a new needle-free approach for insulin delivery. A portable powder needleless injection (PNI) device with an automatic mechanical unit was designed. Its efficiency in delivering insulin was evaluated in alloxan-induced diabetic rabbits. The skin irritation caused by the device was investigated and the results were analyzed in relation to aerodynamic parameters. Inorganic salt-carried insulin powders had hypoglycemic effects, while raw insulin powders were not effective when delivered by PNI, indicating that salt carriers play an important role in the delivery of insulin via PNI. The relative delivery efficiency of phosphate-carried insulin powder using the PNI device was 72.25%. A safety assessment test showed that three key factors (gas pressure, cylinder volume, and nozzle distance) were related to the amount of skin irritation caused by the PNI device. Optimized injection conditions caused minimal skin lesions and are safe to use in practice. The results suggest that PNI has promising prospects as a novel technology for delivering insulin and other biological drugs.

Occurrence of toxigenic fungi and determination of mycotoxins by HPLC-FLD in functional foods and spices in China markets.

Twenty-four samples including 14 functional foods and 10 spices obtained from Chinese markets were examined for their mould profile. The mycotoxin contamination levels were also determined by an optimized HPLC-FLD method. 124 fungal isolates belonging to four different genera were recovered with Aspergillus and Penicillium as predominant fungi, with an incidence of 66.1% and 15.3%, respectively. In functional foods Aspergillus niger section (57.1%) was isolated more frequently, followed by Aspergillus flavi section (50.0%) and Aspergillus ochraceus section (21.4%), with the most contaminated samples being Coix seeds. Similar fungal presence and frequency were encountered in spice with A. niger section group (60.0%) and A. flavi section (40.0%) as main fungi. Cumin and Pricklyash peel samples showed the highest fungal contamination. Four functional foods and three spices were found to be positive at low levels for mycotoxins including aflatoxin B1 (up to 0.26µg/kg) and ochratoxin A (OTA) (5.0µg/kg). The more frequently detected mycotoxin was AFB1 (16.7%).

[Novel method for dynamic monitoring and early-warning on wild resources of traditional Chinese medicines based on price ratio between drug and foodstuff].

OBJECTIVE: To probe into the new idea along with establishment of a novel method for dynamic monitoring and early-warning on the wild resources of traditional Chinese medicines (TCMs). METHOD: The alterations of wild traditional Chinese medicinal resources were assessed through the price ratio between drug and foodstuff (PRDF) indicating the balance between supply and demand of the specific TCMs, referred to the price ration between pork to foodstuff which is used in national monitoring to the balance between pork supply and demand. RESULT: Since the price of rice was tightly controlled by government, it was selected as a relatively stable reference to build the PRDF in order to take away the non-marketing influence to TCMs price such as CPI and inflation rate. The modified relative alteration trend of TCMs price had been researched through comparing different formulae to build PRDF, including absolute average month price of TCMs, month average price ratio of TCMs to foodstuff (rice) , month-on-month change of TCMs to rice, year-on-year change of TCMs to rice, and difference in value of period-on-period change (DVPPC). In the research, Cordyceps, Glycyrrhiza and totally five herbs were selected as model drugs and the price data were collected from 2002 to 2008. The results showed that DVPPC calculated of relative long time window was more sensitive and stable to reflect the relative alteration trend of TCMs price. For instance, the DVPPC of Ligustici showed continuously increase trend in recent years. This suggested appearance of unbalance between supply and demand of Ligustici, and forced policy intervention to maintain reasonable and continuable utilization of Ligustici resource. CONCLUSION: The proposed method and the formula of DVPPC revealed some useful guidance for dynamic monitoring the wild resources of TCMs.

Assessment of the renal protection and hepatotoxicity of rhubarb extract in rats.

AIM OF THE STUDY: Rhubarb is well used to treat chronic renal failure (CRF) in China and Japan, but recent studies reported that the anthraquinone derivatives contained in rhubarb had nephrotoxicity. In this investigation an attempt was made to assess the value and toxic potential of rhubarb to treat CRF. MATERIALS AND METHODS: Histopathologic and biochemical tests combined with toxicokinetic analysis were performed to investigate the nephrotoxic potential and protective effect of rhubarb extract. RESULTS: In normal rat groups, no death was observed and no renal lesion was found after repetitive administration of rhubarb for 3 weeks. The survival rate, pathologic conditions and biochemical indexes of CRF rats treated with rhubarb at two dosages were all improved and significant amelioration was found in the low dosage group compared to the untreated CRF group. Rhein was the mainly absorbable anthraquinone derivative into systemic circulation after oral administration and the area under curve of rhein in CRF groups was lower than that in normal groups at same dosage. CONCLUSIONS: After 3 weeks of administration of rhubarb extract, there was evidence of protective effect to CRF rats, while incidences of hepatotoxicity with minimal to mild hyaline droplets were also observed in normal rats.

[Effects of 3 genosides on bio-thermodynamic expression of splenic lymphocyte in mice].

OBJECTIVE: To establish a new method for screening active ingredients of Chinese herbs by determining different bio-thermodynamic effects of 3 genosides on splenic lymphocyte of mice. METHODS: Using a thermal bioactivity monitoring system, the maximum heat output (mHO), average metabolic heat (MH) and constant of decrease rate (DR) of lymphocyte were determined based on the growth metabolic power-time curve, and the outcomes were verified by MIT. RESULTS: The mHO and MH increased and the DR decreased after lymphocytes being exposed to the 3 genosides in different concentrations, arranged upon their potency as genoside Rg3 > genoside Rg2 > genoside Rg1 (merely insignificant effect). MTT showed the same results. CONCLUSION: Heat activity monitoring system could precisely display the different bio-thermal dynamic effects of 3 genosides on splenic lymphocyte.