Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Transesophageal echocardiography detection of air embolism during endoscopic surgery and validity of hyperbaric oxygen therapy: Case report.

INTRODUCTION: Air embolism has the potential to be serious and fatal. In this paper, we report 3 cases of air embolism associated with endoscopic medical procedures in which the patients were treated with hyperbaric oxygen immediately after diagnosis by transesophageal echocardiography. In addition, we systematically review the risk factors for air embolism, clinical presentation, treatment, and the importance of early hyperbaric oxygen therapy efficacy after recognition of air embolism. PATIENT CONCERNS: We present 3 patients with varying degrees of air embolism during endoscopic procedures, one of which was fatal, with large amounts of gas visible in the right and left heart chambers and pulmonary artery, 1 showing right heart enlargement with increased pulmonary artery pressure and tricuspid regurgitation, and 1 showing only a small amount of gas images in the heart chambers. DIAGNOSES: Based on ETCO2 and transesophageal echocardiography (TEE), diagnoses of air embolism were made. INTERVENTIONS: The patients received symptomatic supportive therapy including CPR, 100% O2 ventilation, cerebral protection, hyperbaric oxygen therapy and rehabilitation. OUTCOMES: Air embolism can causes respiratory, circulatory and neurological dysfunction. After aggressive treatment, one of the 3 patients died, 1 had permanent visual impairment, and 1 recovered completely without comorbidities. CONCLUSIONS: While it is common for small amounts of air/air bubbles to enter the circulatory system during endoscopic procedures, life-threatening air embolism is rare. Air embolism can lead to serious consequences, including respiratory, circulatory, and neurological impairment. Therefore, early recognition of severe air embolism and prompt hyperbaric oxygen therapy are essential to avoid its serious complications.

Qualitative and quantitative analyses of quinones in multi-origin Rubia species by ultra-performance liquid chromatography-tandem mass spectrometry combined with chemometrics.

Rubia species are one of the important multi-origin phytomedicines having both economical and medicinal values in many countries. Quinones are the predominant bioactive constituents of these species. Therefore, accurate analysis of these quinones is critical to quality control, clinical, and commercial applications of Rubia species. In this study, a sensitive and efficient ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method in positive and negative multiple reaction monitor (+/-MRM) modes was firstly developed for the characterization of 45 quinones and the quantification of 24 quinones from Rubia plants. The chromatographic separation was achieved on a Waters ACQUITY UPLC® BEH C18 column by using a gradient elution with a mobile phase consisting of 0.1 % formic acid in water and acetonitrile. The results indicated that quinones in multi-origin Rubia samples were different, but 10 quinones existed in all samples. R. cordifolia, which is a unique official medicinal material in Chinese Pharmacopeia, contained the most number of quinones among all the Rubia species. R. podantha and R. sylvatica had the next highest number of quinones, implying that these species could be used as alternatives for R. cordifolia. Chemometric approaches were applied to evaluate the chemical relationship between the Rubia samples based on the constituent quinones. In this study, a UPLC-QqQ-MS/MS method in the MRM mode has been developed for the analysis of Rubia species-derived quinones, which not only contributes to quality control and discrimination of Rubia species, but also suggests the potential of these species in clinical and commercial applications.

Effects of dietary hydrolyzed yeast (Rhodotorula mucilaginosa) on growth performance, immune response, antioxidant capacity and histomorphology of juvenile Nile tilapia (Oreochromis niloticus).

An 8 weeks feeding experiment was conducted to evaluate the effects of dietary supplementation with hydrolyzed yeast (HY) (Rhodotorula mucilaginosa) on growth performance, hematological parameters, immune response and antioxidant ability of juvenile Nile tilapia. Five isonitrogenous and isolipidic diets (32% protein and 4% lipid) with different levels (0%, 0.125%, 0.25%, 0.5%, 1%) of HY were formulated. Each diet was randomly assigned to quadruplicate groups of fish (initial body weight 19.1 ±â€¯0.01 g). Results indicated that significantly higher specific growth rate (SGR) and lower feed conversion rate (FCR) were obtained in fish fed 1% HY diet than that of fish fed 0% HY diet (P < 0.05). Fish fed 0.25% HY diet showed the lowest value of hepatopancreas somatic indices (HSI) and significantly lower than that of fish fed 0% HY diet (P < 0.05). Meanwhile, protein and ash in the whole-body content of fish fed 1% HY diet was significantly higher than that of fish fed 0%-0.5% HY diets. Serum immunological parameters showed that the lysozyme (LZM) activity and Complement C3 content were significantly increased by dietary supplementation of 0.5%-1% HY (P < 0.05). However, dietary supplementation with 0.125%-1% HY significantly decreased the activity of myeloperoxidase (MPO) (P < 0.05). Antioxidant status in serum and liver was significantly enhanced by dietary supplementation of 0.25%-1% HY through the remarkably improved superoxide dismutase (SOD) activity both in serum and liver, the raised total antioxidative capacity (T-AOC) of serum as well as the notably reduced malondialdehyde (MDA) content in the liver (P < 0.05). However, T-AOC in the liver was not significantly influenced among all diet treatments (P > 0.05). Villi height and intraepithelial lymphocytes (IEFs) of mid-intestine were significantly higher in fish fed 0.5%-1% HY diets (P < 0.05). The challenge test demonstrated the enhanced protection against Streptococcus iniae strain by the obtained higher cumulative survival rate. In conclusion, dietary supplementation of 1% HY could maintain the better growth performance, nutrient composition as well as immune response and antioxidant capacity for juvenile Nile tilapia.

Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/ß-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling.

Renal fibrosis is a common end point of the progression of chronic kidney disease (CKD). Suppressing the development and progression of renal fibrosis is essential in the treatment of kidney disease. Our previous study demonstrated that the ethyl acetate extract of the surface layer of Poria cocos exhibited beneficial antitubulointerstitial fibrosis. In this study, we isolated new diterpene (PZF) and triterpenes (PZG and PZH) and examined their antifibrotic effect. TGF-ß1 upregulated the collagen I protein expression in HK-2 cells, and PZG and PZH treatment significantly inhibited the upregulated collagen I expression (TGF group 0.59 ± 0.08 vs TGF+PZG group 0.36 ± 0.08, P < 0.01; TGF+PZH group 0.39 ± 0.12, P < 0.01). Triterpenes, PZG and PZH, exhibited a stronger inhibitory effect on renal fibrosis and podocyte injury than PZF. PZG and PZH further showed a stronger inhibitory effect on the activation of the renin-angiotensin system (RAS) than PZF. Additionally, PZG and PZH markedly inhibited the activation of Wnt/ß-catenin signaling, which played an important role in fibrogenesis. Interestingly, PZG and PZH suppressed the TGF-ß/Smad pathway by selectively inhibiting the phosphorylation of Smad3 through blocking the interactions of SARA with TGFßI and Smad3. The analysis of the structure-activity relationship demonstrated that their antifibrotic effects were closely associated with the first six-membered ring structure and the number of carboxyl groups in this type of compounds. Additionally, fifteen known triterpenes were identified. These novel tetracyclic triterpenoid compounds provided the potential lead compounds for the research and development of antifibrosis drug, and they possessed the potential to be utilized as RAS inhibitors.

Cardioprotective potential of Dendrobium officinale Kimura et Migo against myocardial ischemia in mice.

Dendrobium officinale Kimura et Migo has been used for thousands of years to promote body fluid production; however, little is currently known regarding its effects on the heart. The present study aimed to explore the cardioprotective potential of the water extract of Dendrobium officinale Kimura et Migo (DOE) on myocardial ischemia in mice. A mouse model of myocardial ischemia was induced following ligation of the left anterior descending coronary artery. Prior to the operation, mice were administered a vehicle or DOE for 2 weeks. Following the operation, ST elevation was measured. To estimate the extent of myocardial damage, infarct size analysis and histopathological examination were performed. The activities of cardiac marker enzymes [creatine kinase (CK)­MB and lactate dehydrogenase (LDH)] and antioxidative indicators [malondialdehyde (MDA) and superoxide dismutase (SOD)] were also analyzed to explore the underlying mechanisms. Treatment with DOE decreased infarct size and the number of apoptotic cardiomyocytes; reduced serum CK­MB, LDH and MDA activities; and increased SOD levels. According to western blotting, DOE conferred protection against myocardial ischemic injury via the regulation of Meis1 expression. These results indicated that DOE may exert potential cardioprotective effects against myocardial ischemia; these effects may be associated with its antioxidant activity, and its ability to inhibit cardiac cell apoptosis and to regulate Meis1 expression.

The Therapeutic Effects of the Chinese Herbal Medicine, Lang Chuang Fang Granule, on Lupus-Prone MRL/lpr Mice.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that leads to severe multiorgan damage. Lang Chuang Fang (LCF) is a Chinese herbal medicine that is clinically prescribed for treating SLE. In this study, we examined the therapeutic effects of LCF granule on lupus-prone MRL/lpr mice. Female mice were randomly separated into six groups, and LCF treatment groups received LCF granule at the dosage of 0.97 g/kg/d, 1.95 g/kg/d, and 3.90 g/kg/d, respectively. Here, we found that, compared to the MRL/lpr mice, both the spleen coefficient and thymus coefficient were reduced in the LCF granule-treated mice. There was a marked downregulation in CRP and anti-dsDNA autoantibody and an evident upregulation of CH50 in LCF granule-treated mice. LCF granule treatment also obviously reduced the proteinuria, BUN, and SCr levels in MRL/lpr mice at the dosage of 0.97 g/kg/d, 1.95 g/kg/d, and 3.90 g/kg/d, indicating that LCF granule alleviated the renal injury of MRL/lpr mice. Furthermore, LCF granule decreased p65 NF-κB levels and increased Sirt1 and Nrf2 levels in the kidney tissues of MRL/lpr mice, which might elucidate the beneficial effects of LCF on lupus nephritis. In conclusion, this study demonstrates that LCF granule has therapeutic effects on lupus-prone MRL/lpr mice.

An integrated lipidomics and metabolomics reveal nephroprotective effect and biochemical mechanism of Rheum officinale in chronic renal failure.

Chronic renal failure (CRF) is a major public health problem worldwide. Earlier studies have revealed salutary effects of rhubarb extracts in CRF. In this study, we employed lipidomic and metabolomic approaches to identify the plasma biomarkers and to determine the effect of treatment with petroleum ether, ethyl acetate and n-butanol extracts of rhubarb in a rat model of CRF with adenine-induced chronic tubulointerstitial nephropathy. In addition, clinical biochemistry, histological evaluation and pro-fibrotic protein expression were analyzed. Significant changes were found between the CRF and control groups representing characteristic phenotypes of rats with CRF. Treatment with the three rhubarb extracts improved renal injury and dysfunction, either fully or partially reversed the plasma metabolites abnormalities and attenuated upregulation of pro-fibrotic proteins including TGF-ß1, α-SMA, PAI-1, CTGF, FN and collagen-1. The nephroprotective effect of ethyl acetate extract was better than other extracts. The differential metabolites were closely associated with glycerophospholipid, fatty acid and amino acid metabolisms. The results revealed a strong link between renal tubulointerstitial fibrosis and glycerophospholipid metabolism and L-carnitine metabolism in the development of CRF. Amelioration of CRF with the three rhubarb extracts was associated with the delayed development and/or reversal the disorders in key metabolites associated with adenine-induced CRF.

Metabolomics insights into chronic kidney disease and modulatory effect of rhubarb against tubulointerstitial fibrosis.

Chronic kidney disease (CKD) is a major public health problem worldwide. Rhubarb has been shown to have nephroprotective and anti-fibrotic activities in patients with CKD. However, bioactive fractions and biochemical mechanism of anti-fibrotic properties of rhubarb remain unclear. Here we applied ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry together with univariate and multivariate statistical analyses to investigate the urinary metabolite profile in rats with adenine-induced CKD treated with the petroleum ether (PE)-, ethyl acetate (EA)- and n-butanol (BU)- extracts of rhubarb. Significant differences in renal function, kidney histopathology as well as metabolic profiles were observed between CKD and control rats. Changes in these parameters reflected characteristic phenotypes of CKD rats. We further identified a series of differential urinary metabolites for CKD rats, suggesting metabolic dysfunction in pathway of amino acid, purine, taurine, and choline metabolisms. Treatment with EA, BU and PE extracts of rhubarb improved renal function and histopathological abnormalities including interstitial fibrosis and inflammation, and either fully or partially reversed the abnormalities of the urinary metabolites. Among them, the nephroprotective effect of EA extract was stronger than BU and PE extracts. This work provides important mechanistic insights into the CKD and nephroprotective effects of different rhubarb extract against tubulo-interstitial fibrosis.

[HPLC determination of four flavonoids in rat plasma after oral ecliptae herba extract].

OBJECTIVE: To establish an HPLC method for determination of four flavonoids in rat plasma after oral Ecliptae Herba extract. METHODS: HPLC separation was carried out in a Neocleodur 100-5 C18 column (250 mm x 4.6 mm, 5 microm) with mobile phase A (consisting of methanol-0.2% phosphoric acid = 50:50) and mobile phase B (acetonitrile)with gradient elution at the flow rate of 1.0 mL/min. The detection wavelength was 350 nm and the column temperature was maintained at 40 degrees C. RESULTS: There were good linear relationships between concentration and peak area ratio of luteolin, apigenin, scutellarein and diosmetin in the ranges of 0.02-50 microg/mL with the recovery rates of 71.5%-90.2%. CONCLUSION: This method is rapid, accurate and reproducible for determination of luteolin, apigenin, scutellarein and diosmetin in rat plasma and study on pharmacokinetics of Ecliptae Herba extract.

Metabonomic study of biochemical changes in the rat urine induced by Pinellia ternata (Thunb.) Berit.

We adopted an ultra performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC Q-TOF/MS) metabonomics approach to study metabonomic features of rats induced by orally administered Pinellia ternata (Thunb.) Berit. (BX). The integrated urinary MS data were analyzed via principal component analysis (PCA) and partial least squares-discriminant analysis (OPLS-DA) to identify the differential metabolites. Ten potential biomarkers were identified within complex sample matrix of urine. The identified biomarkers indicated the perturbations of tryptophan, phenylacetylglycine and pantothenic acid metabolism in BX-induced rats. The biomarkers that were found to be changed with the passage of time were explained tentatively based on previous study.

General toxicity of Pinellia ternata (Thunb.) Berit. in rat: a metabonomic method for profiling of serum metabolic changes.

ETHNOPHARMACOLOGICAL RELEVANCE: BX is a traditional Chinese medicine (TCM) from the plant Pinellia ternata(Thunb.) Berit. It has been traditionally used to treat cough, vomiting, infection and inflammation. Despite of its potentially clinical utility, it also has many side effects and toxicity. AIM OF THE STUDY: We propose here an ultra performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC Q-TOF/MS) metabonomics approach to elucidate the toxicity in rats induced by orally administered BX in multiple organs including the kidney, liver, and heart. MATERIALS AND METHODS: Serum samples were collected from Sprague-Dawley male rats exposed to BX (6g/kg/day, n=10) and healthy controls (n=10) at the 48 h, 144 h, 240 h, and 336 h postdose for LC/MS analyses. Through principal component analysis and orthogonal partial least squares-discriminant analysis of the integrated serum MS data, we distinguished the BX group from the healthy control group and identified the differential metabolites and pertinent altered biological pathways in response to the herbal toxin. The liver, kidney, heart were assessed using conventional histopathological examinations at the end point of the experiment. The serum samples at the 336 h postdose were assessed using biochemistry test. RESULTS: Significant differences in the serum levels of phospholipids, amino acids, L-carnitine and L-acetylcarnitine were observed in BX-induced rats, indicating the perturbations of phospholipid metabolism, amino acid metabolism and carnitine metabolism in BX-induced rats. CONCLUSIONS: In the paper, we used metabonomics approach to study the toxicity of BX for the first time. With blood biochemistry, histopathological examinations and metabonomics methods, we validated that oral administration of crude BX caused no obvious liver and kidney toxicity in SD rats. BX may possess certain cardio toxicity in SD rats. The metabolism changes suggested that metabonomic approach was a promising tool to study and diagnose TCM-induced toxicity.

Two new compounds isolated from Liriope muscari.

Two new compounds, (2S,3R)-methyl 7-hydroxy-2-(4-hydroxy-3-methoxy-phenyl)-3-(hydroxymethyl)-2,3-dihydrobenzofuran-5-carboxylate (1) and (4R,5S)-5-(3-hydroxy-2,6-dimethylphenyl)-4-isopropyldihydrofuran-2-one (2), tentatively named norcurlignan and limlactone, respectively, were isolated from Liriope muscari, together with the known compound (-)-pinoresinol (3). The structures of these compounds were elucidated and characterized on the basis of 1D NMR, 2D NMR, CD and MS data. The in vitro antioxidant activities of compounds 1-3 were assessed by the DPPH and ABTS scavenging methods.