Ya-Long Feng

Ultra performance liquid chromatography-based metabonomic study of therapeutic effect of the surface layer of Poria cocos on adenine-induced chronic kidney disease provides new insight into anti-fibrosis mechanism.

The surface layer of Poria cocos (Fu-Ling-Pi, FLP) is commonly used in traditional Chinese medicine and its diuretic effect was confirmed in rat. Ultra performance liquid chromatography/quadrupole time-of-flight high-sensitivity mass spectrometry and a novel mass spectrometryElevated Energy data collection technique was employed to investigate metabonomic characteristics of chronic kidney disease (CKD) induced from adenine excess and the protective effects of FLP. Multiple metabolites are detected in the CKD and are correlated with progressive renal injury. Among these biomarkers, lysoPC(18∶0), tetracosahexaenoic acid, lysoPC(18∶2), creatinine, lysoPC (16∶0) and lysoPE(22∶0/0∶0) in the FLP-treated group were completely reversed to levels in the control group which lacked CKD. Combined with biochemistry and histopathology results, the changes in serum metabolites indicate that the perturbations of phospholipids metabolism, energy metabolism and amino acid metabolism are related to adenine-induced CKD and to the interventions of FLP on all the three metabolic pathways. FLP may regulate the metabolism of these biomarkers, especially their efficient utilization within the context of CKD. Furthermore, these biomarkers might serve as characteristics to explain the mechanisms of FLP.

Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE

Poria cocos epidermis is one of ancient traditional Chinese medicines (TCMs), which is usually used for the treatment of chronic kidney disease (CKD) for thousands of years in China. A metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry (UPLC Q-TOF/HSMS) and a mass spectrometry(Elevated Energy) (MS(E)) data collection technique was developed to obtained a systematic view of the development and progression of CKD and biochemistry mechanism of therapeutic effects of P. cocos epidermis (Fu-Ling-Pi, FLP). By partial least squares-discriminate analysis, 19 metabolites were identified as potential biomarkers of CKD. Among the 19 biomarkers, 10 biomarkers including eicosapentaenoic acid, docosahexaenoic acid, lysoPC(20:4), lysoPC(18:2), lysoPC(15:0), lysoPE(20:0/0:0), indoxyl sulfate, hippuric acid, p-cresol sulfate and allantoin were reversed to the control level in FLP-treated groups. The study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as fatty acid metabolism, phospholipid metabolism, purine metabolism and tryptophan metabolism. This work was for the first time to investigate the FLP therapeutic effect based on metabonomics technology, which is a potentially powerful tool to study the TCMs.

Metabolomics in dyslipidemia.

Hyperlipidemia is an important public health problem with increased incidence and prevalence worldwide. Current clinical biomarkers, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol lack the necessary specificity and sensitivity and only increase significantly after serious dyslipidemia. Therefore, sensitive biomarkers are needed for hyperlipidemia. Hyperlipidemia-specific biomarkers would improve clinical diagnosis and therapeutic treatment at early disease stages. The aim of metabolomics is to identify untargeted and global small-molecule metabolite profiles from cells, biofluids, and tissues. This method offers the potential for a holistic approach to improve disease diagnoses and our understanding of underlying pathologic mechanisms. This review summarizes analytical techniques, data collection and analysis for metabolomics, and metabolomics in hyperlipidemia animal models and clinical studies. Mechanisms of hypolipemia and antilipemic drug therapy are also discussed. Metabolomics provides a new opportunity to gain insight into metabolic profiling and pathophysiologic mechanisms of hyperlipidemia.

Diuretic and anti-diuretic activities of the ethanol and aqueous extracts of Alismatis rhizoma

ETHNOPHARMACOLOGICAL RELEVANCE Alismatis rhizoma or Alisma orientale (Zexie in Chinese), the dried rhizome of Alisma orientale Juzepzuk (Alismataceae), is a well-known traditional Chinese medicine and is used as an agent for diuresis and for excreting dampness in Asia and Europe. In this paper, we report the diuretic activities of the ethanol extract (EE) and the aqueous extract (AE) of A. rhizoma (AR). MATERIALS AND METHODS The EE and AE were orally administered to rats. The urinary excretion rate and pH, and electrolyte excretion were measured in the urine of saline-loaded rats. RESULTS The results showed that EE could increase the urine output at 2.5, 5 and 10mg/kg doses but decrease the urine output at 20, 40 and 80mg/kg doses compared with the control group. The 5 and 10mg/kg doses of EE increased the urine electrolyte excretion, but the effects on Na(+)/K(+) values were too weak to reach statistical significance. The Na(+) excretion and Cl(-) excretion were markedly decreased with the 20, 40 and 80mg/kg doses of EE, but the effect on K(+) excretion was notably slight. All of the tested doses of AE produced an increase in urinary excretion, but the increase did not reach statistical significance. CONCLUSIONS This study identified that EE but not AE presents a notable diuretic effect, and EE had diuretic and anti-diuretic effects, which appears to be related to the sodium-chloride co-transporter in the renal distal convoluting tubule. This study demonstrated for the first time that the EE of AR has a dual effect on renal function, including promotion of diuretic activity at lower doses and inhibiting diuretic activity at higher doses, and the AR dose should be given more attention in clinical applications. This study will play a critical and guiding role in the dosing of AR as a diuretic drug in clinical applications.

Diuretic and anti-diuretic activities of fractions of Alismatis rhizoma

ETHNOPHARMACOLOGICAL RELEVANCE Alismatis rhizoma or Alisma orientale (Zexie in Chinese), the dried rhizome of Alisma orientale Juzepzuk (Alismataceae), is a well-known traditional Chinese medicine and is used as an agent for diuresis and for excreting dampness in China and Japan. In this paper, we report the diuretic activities of the petroleum ether fraction, the ethyl acetate fraction, the n-buthanol fraction, and the remaining fraction, of the ethanol extract of Alismatis rhizoma (AR). MATERIALS AND METHODS The single dose of the petroleum ether fraction, the ethyl acetate fraction, the n-buthanol fraction, and the remaining fraction, of the ethanol extract of AR were orally administered to rats. Urinary excretion rate, pH and electrolyte excretion were measured in the urine of saline-loaded rats. RESULTS In this study, the 100 and 400mg/kg doses of the ethyl acetate fraction and the 12.5, 25 and 50mg/kg doses of the n-butanol fraction all produced an increase in urine volume excretion, and all produced a remarkable increase in urine electrolyte excretion. Although the 800mg/kg doses of the ethyl acetate fraction, the 75 and 100mg/kg doses of the n-butanol fraction and the 12.5, 25 and 50mg/kg doses of the remaining fraction significantly decreased the urine output in 6h, the urine Na(+) and Cl(-) excretion were markedly decreased with the n-butanol fraction (75 and 100mg/kg doses) and the remaining fraction (12.5, 25 and 50mg/kg doses) while the ethyl acetate fraction at 800mg/kg doses had slight effect on urine electrolyte excretion. The petroleum ether fraction did not show remarkable diuretic activity in comparison with control group. CONCLUSIONS Our present study determined that the ethyl acetate fraction and the n-butanol fraction present notable diuretic effects, and we found a dual effect on renal function showed by AR, including promoting diuretic activity and inhibiting diuretic activity. The components with strong polarities in AR may have anti-diuretic activities, which might be an effect of promoting the sodium-chloride co-transporter in the distal tubule.

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

Cloud-Point Extraction Combined with Liquid Chromatography for the Determination of Ergosterol, a Natural Product with Diuretic Activity, in Rat Plasma, Urine, and Faeces

Ergosterol from many medicinal fungi has been demonstrated to possess a variety of pharmacological activities in vivo and in vitro. A new method based on cloud-point extraction has been developed, optimized and validated for the determination of ergosterol in rat plasma, urine and faeces by liquid chromatography. The non-ionic surfactant Triton X-114 was chosen as the extract solvent. The chromatographic separation was performed on an Inertsil ODS-3 analytical column with a mobile phase consisting of methanol and water (98 : 2, v/v) at a flow rate of 1 mL/min. The methodology was validated completely. The results indicated good performance in terms of specificity, linearity, detection and quantification limits, precision and accuracy. The method was successfully applied to the pharmacokinetic studies of ergosterol in rats. The results indicate that the ergosterol levels in feces are much higher than those in plasma and urine of the rat.

New insights into TGF-β/Smad signaling in tissue fibrosis

Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

Natural Products as a Source for Antifibrosis Therapy

Although fibrosis is a final pathological feature of many chronic diseases, few interventions are available that specifically target the pathogenesis of fibrosis. Natural products are becoming increasingly recognized as effective therapies for fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. We describe some new profibrotic mechanisms and corresponding therapeutic targets using natural products. Interleukin, ephrin-B2, Gas6/TAM, Wnt/β-catenin, hedgehog pathway, PPARγ, lysophosphatidic acid, and CTGF are promising therapeutic targets. Natural products can target these mediators and inhibit chronic inflammation, myofibroblast activation, epithelial-mesenchymal transition, and extracellular matrix accumulation to alleviate fibrosis. Of note, natural products have the potential to inhibit fibrosis in one organ, simultaneously targeting fibrosis in multiple other organs, which provides us new strategies to find antifibrotic drugs.

Natural products for the prevention and treatment of kidney disease

BACKGROUND Chronic kidney disease (CKD) is one of the common causes resulting in a high morbidity and mortality. Renal fibrosis is the main pathological features of CKD. Natural products have begun to gain widely popularity worldwide for promoting healthcare and preventing CKD, and have been used as a conventional or complementary therapy for CKD treatment. PURPOSE The present paper reviewed the therapeutic effects of natural products on CKD and revealed the molecular mechanisms of their anti-fibrosis. METHODS All the available information on natural products against renal fibrosis was collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Splinker, etc.). RESULTS Accumulated evidence demonstrated that natural products exhibited the beneficial effects for CKD treatment and against renal fibrosis. This review presents an overview of the molecular mechanism of CKD and natural products against renal fibrosis, followed by an in-depth discussion of their molecular mechanism of natural products including isolated compounds and crude extracts against renal fibrosis in vitro and in vivo. A number of isolated compounds have been confirmed to retard renal fibrosis. CONCLUSION The review provides comprehensive insights into pathophysiological mechanisms of CKD and natural products against renal fibrosis. Particular challenges are presented and placed within the context of future applications of natural products against renal fibrosis.