A network pharmacology-based study on the mechanism of astragaloside IV alleviating renal fibrosis through the AKT1/GSK-3ß pathway.

ETHNOPHARMACOLOGICAL REVELVANCE: Astragaloside IV, a glycoside derived from Astragalus membranaceus, has anti-renal fibrosis effects. However, its mechanism of action has not yet been fully elucidated. AIM OF THE STUDY: The purpose of this study was to investigate the anti-fibrotic effect of AS-IV and to clarify its underlying mechanism. MATERIALS AND METHODS: The network pharmacology method, molecular docking and surface plasmon resonance (SPR) was used to identify potential targets and pathways of AS-IV. A unilateral ischemia-reperfusion injury (UIRI) animal model, as well as TGF-ß1-induced rat renal tubular epithelial cells (NRK-52E) and renal fibroblasts (NRK-49F) were used to investigate and validate the anti-fibrotic activity and pharmacological mechanism of AS-IV. Network pharmacology was performed to construct a drug-target-pathway network. The anti-fibrosis effect of AS-IV was determined using hematoxylin-eosin (H&E) and MASSON staining, as well as immunostaining methods. qRT-PCR and western blotting were used to elucidate and validate the mechanism of AS-IV. RESULTS: Network pharmacology revealed that the PI3K/AKT pathway is an important pathway in AS-IV. AS-IV inhibited the expression of α-SMA, collagen I, and fibronectin in NRK-52E, NRK-49F, and UIRI rats, and reduced serum creatinine and blood urea nitrogen levels in UIRI rats. AS-IV inhibited AKT phosphorylation, blocked GSK-3ß phosphorylation, and restored GSK-3ß activity, which contributed to the degradation of ß-catenin, thereby preventing epithelial-mesenchymal transition (EMT). CONCLUSION: Astragaloside IV alleviated renal fibrosis through the AKT1/GSK-3ß pathway. In addition, our findings indicate that the network pharmacology method is a powerful tool for exploring the pharmacological mechanisms of drugs.

An integrated network pharmacology and cell metabolomics approach to reveal the role of rhein, a novel PPARα agonist, against renal fibrosis by activating the PPARα-CPT1A axis.

BACKGROUND: Rhein, an anthraquinone compound, displays extensive antifibrotic effects; however, its potential mechanisms are not fully understood. In this study, we explored the underlying molecular mechanism of action of rhein. METHOD: An integrated network pharmacology and cell metabolomics approach was developed based on network pharmacology and bioinformatics method, and then successfully applied to speculate the potential targets of rhein and construct a rhein-target-metabolic enzyme-metabolite network. Thereafter, the antifibrotic mechanism of rhein was validated in TGF-ß- and oleic acid- induced HK-2 and NRK-52E cells in vitro as well as a unilateral ischemia-reperfusion injury Sprague-Dawley rat model. RESULTS: Based on the construction of the rhein-target-metabolic enzyme-metabolite network, we found that rhein played an antifibrotic role through the PPAR-α-CPT1A-l-palmitoyl-carnitine axis. In vitro experiments demonstrated that rhein effectively activated the expression of PPARα and its downstream proteins (CPT1A and ACOX1) to alleviate lipid accumulation and fibrosis development. In vivo experiments indicated that rhein attenuated renal fibrosis mainly by activating the fatty acid oxidation pathway and improving lipid metabolism. CONCLUSION: Taken together, our findings reveal that rhein is a novel agonist of PPARα, which contributes to its renoprotection through the regulation of the PPARα-CPT1A axis. Moreover, our study provides a novel insight into an integrated network pharmacology-metabolomics strategy for uncovering the pharmacological mechanisms of drugs from the system perspective.

Pharmacokinetics and Pharmacodynamics of the Combination of Rhein and Curcumin in the Treatment of Chronic Kidney Disease in Rats.

Objectives: The interaction between the components of traditional Chinese medicine (TCM) is an important basis for their synergy. Rhein and curcumin exert various pharmacological activities, including anti-tumour, anti-inflammatory, antioxidant, anti-fibrosis and renoprotective effects. However, no investigation has reported the synergistic anti-fibrosis effect yet. This study aims at determine the pharmacokinetics and pharmacodynamics of the combination of rhein and curcumin in the treatment for chronic kidney disease in rats. Design: Fifty two male Sprague-Dawley (SD) rats were randomly divided into rhein group, curcumin group and their combination group for pharmacodynamics studies. HE and Masson staining was conducted to observe the changes of renal morphology. Kits were used to detect the level of urea nitrogen (BUN) and creatinine (Scr). For pharmacokinetic study, 36 SD rats were randomly divided into rhein group, curcumin group and a combination group, the content of rhein and curcumin in plasma and renal tissue was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In additon, molecular docking method and cell experiments was used to disclose the interaction mechanism between curcumin and rhein. Results: The pharmacodynamic results showed that the degree of renal fibrosis was improved obviously by co-administration rhein and curcumin. Meanwhile, compared to single administration, the Cmax and AUC of rhein and curcumin in plasma and renal tissue were enhanced significantly after co-administration. Moreover, the result of molecular docking and cell experiments showed that both two compounds could interact with P-gp, CYP2C9 and CYP2C19. Conclusion: Together, these findings demonstrated that rhein and curcumin had a synergistic effect in ameliorateing chonic kidney disease, providing an important explanation on the synergistic mechanism of curcumin and rhein from a pharmacokinetic viewpoint.

China suboptimal health cohort study: rationale, design and baseline characteristics.

BACKGROUND: Suboptimal health status (SHS) is a physical state between health and disease, characterized by the perception of health complaints, general weakness, chronic fatigue and low energy levels. SHS is proposed by the ancient concept of traditional Chinese medicine (TCM) from the perspective of preservative, predictive and personalized (precision) medicine. We previously created the suboptimal health status questionnaire 25 (SHSQ-25), a novel instrument to measure SHS, validated in various populations. SHSQ-25 thus affords a window of opportunity for early detection and intervention, contributing to the reduction of chronic disease burdens. METHODS/DESIGN: To investigate the causative effect of SHS in non-communicable chronic diseases (NCD), we initiated the China suboptimal health cohort study (COACS), a longitudinal study starting from 2013. Phase I of the study involved a cross-sectional survey aimed at identifying the risk/protective factors associated with SHS; and Phase II: a longitudinal yearly follow-up study investigating how SHS contributes to the incidence and pattern of NCD. RESULTS: (1) Cross-sectional survey: in total, 4313 participants (53.8 % women) aged from 18 to 65 years were included in the cohort. The prevalence of SHS was 9.0 % using SHS score of 35 as threshold. Women showed a significantly higher prevalence of SHS (10.6 % in the female vs. 7.2 % in the male, P < 0.001). Risk factors for chronic diseases such as socioeconomic status, marital status, highest education completed, physical activity, salt intake, blood pressure and triglycerides differed significantly between subjects of SHS (SHS score ≥35) and those of ideal health (SHS score <35). (2) Follow up: the primary and secondary outcomes will be monitored from 2015 to 2024. CONCLUSIONS: The sex-specific difference in prevalence of SHS might partly explain the gender difference of incidence of certain chronic diseases. The COACS will enable a thorough characterization of SHS and establish a cohort that will be used for longitudinal analyses of the interaction between the genetic, lifestyle and environmental factors that contribute to the onset and etiology of targeted chronic diseases. The study together with the designed prospective cohort provides a chance to characterize and evaluate the effect of SHS systemically, and it thus generates an unprecedented opportunity for the early detection and prevention of chronic disease.

Toxic effects of trace elements on newborns and their birth outcomes.

Some trace elements are essential for newborns, their deficiency may cause abnormal biological functions, whereas excessive intakes due to environmental contamination may create adverse health effects. This study was conducted to measure the levels of selected trace elements in Chinese fish consumers by assessing their essentiality and toxicity via colostrum intake in newborns, and evaluated the effects of these trace elements on birth outcomes. Trace elements in umbilical cord serum and colostrum of the studied population were relatively high compared with other populations. The geometric means (GM) of estimated daily intake (EDI, mgday(-1)) of the trace elements were in the safe ranges for infant Dietary Reference Intakes (DRIs) recommended by the United States Food and Drug Administration (FDA). When using total dietary intake (TDI, mgkg(-1)bwday(-1)), zinc (Zn) (0.880mgkg(-1)bwday(-1)) and selenium (Se) (6.39×10(-3)mgkg(-1)bwday(-1)) were above the Reference Doses (RfD), set by the United States Environmental Protection Agency (EPA). Multivariable linear regression analyses showed that Se was negatively correlated with birth outcomes. Our findings suggested that overloading of trace elements due to environmental contamination may contribute to negative birth outcomes.

[Exertion of dredging and guiding technique in Zhu Bing Yuan Hou Lun ( General Treatise on Causes and Manifestations of All Diseases)].

Zhu Bing Yuan Hou Lun (General Treatise on Causes and Manifstations of All Diseases) is an immortal monograph of clinical pathology and science of clinical manifestations. It always encloses health preserving method and dredging and guiding technique for preventing and treating disease following the description of the various syndromes of a disease. Many contents about dredging and guiding technique recorded in the book were lost already, and the contents fully exert the technique. For instance, it explains the concrete method of interpreting the skill of doing the technique, elucidates the theories, explains the basic terms straightaway, and encloses the doctor's advises after doing the technique. The book emphasizes swallowing saliva when regulating qi, and preserving thoughts are combined when doing the technique, as well as diet indications and contraindications. The "six- word pithy knack" is determined firstly in the book and paired with different Zang-fu organs, as well as emphasizing the performance of the technique based on syndrome differentiation.