Calcitriol ameliorates damage in high-salt diet-induced hypertension: Evidence of communication with the gut-kidney axis.

Several studies have established a link between high-salt diet, inflammation, and hypertension. Vitamin D supplementation has shown anti-inflammatory effects in many diseases; gut microbiota is also associated with a wide variety of cardiovascular diseases, but potential role of vitamin D and gut microbiota in high-salt diet-induced hypertension remains unclear. Therefore, we used rats with hypertension induced by a high-salt diet as the research object and analyzed the transcriptome of their tissues (kidney and colon) and gut microbiome to conduct an overall analysis of the gut-kidney axis. We aimed to confirm the effects of high salt and calcitriol on the gut-kidney immune system and the composition of the intestinal flora. We demonstrate that consumption of a high-salt diet results in hypertension and inflammation in the colon and kidney and alteration of gut microbiota composition and function. High-salt diet-induced hypertension was found to be associated with seven microbial taxa and mainly associated with reduced production of the protective short-chain fatty acid butyrate. Calcitriol can reduce colon and kidney inflammation, and there are gene expression changes consistent with restored intestinal barrier function. The protective effect of calcitriol may be mediated indirectly by immunological properties. Additionally, the molecular pathways of the gut microbiota-mediated blood pressure regulation may be related to circadian rhythm signals, which needs to be further investigated. An innovative association analysis of the microbiota may be a key strategy to understanding the association between gene patterns and host.

[Expert consensus on Tongsaimai Tablets/Capsules in treatment of peripheral vascular diseases in clinical practice].

Tongsaimai Tablets/Capsules are composed of Lonicerae Japonicae Flos, Angelicae Sinensis Radix, Achyranthis Bidentatae Radix, Codonopsis Radix, Dendrobii Caulis, Astragali Radix, Scrophulariae Radix, and Glycyrrhizae Radix et Rhizoma, and are effective in promoting blood circulation, removing blood stasis, supplementing Qi, and nourishing Yin. It is widely used in the treatment of peripheral vascular diseases. With 40 years of clinical application, it has accumulated substantial research data and application experience. Its good clinical efficacy and pharmacoeconomic benefits in improving the clinical symptoms of peripheral vascular diseases have been confirmed by relevant research. Meanwhile, this drug has also been recommended by many expert consensus, guidelines, and teaching materials, serving as one of the most commonly used Chinese patent medicines in clinical practice. To further improve the understanding of the drug among clinicians and properly guide its clinical medication, the China Association of Chinese Medicine took the lead and organized experts to jointly formulate this expert consensus. Based on the questionnaire survey of clinicians and the systematic review of research literature on Tongsaimai Tablets/Capsules with clinical problems in the PICO framework, the consensus, combined with expert experience, concludes recommendations or consensus suggestions by GRADE system with the optimal evidence available through the nominal group technique. This consensus defines the indications, usage, dosage, course of treatment, medication time, combined medication, and precautions of Tongsaimai Tablets/Capsules in the treatment of peripheral vascular diseases, and explains the safety of its clinical application. It is recommended for clinicians and pharmacists in the peripheral vascular department(vascular surgery), traditional Chinese medicine surgery(general surgery), and endocrinology department of hospitals at all levels in China.

Distribution, Composition, Sources, and Potential Ecological Risks of PAHs in the Sediments of the Lanzhou Reach of the Yellow River, China.

The distribution, composition, sources, and potential ecological risks of polycyclic aromatic hydrocarbons (PAHs) in the sediments of the Lanzhou Reach of the Yellow River, China were investigated. The total concentration of the 18 individual PAHs (∑18PAHs) in the sediments ranged from 638 to 1620 ng/g, with a mean value of 901 ng/g. The pollution level of PAHs in the sediments was low to moderate. Spatially, the distribution of PAHs in the sediments showed an increasing trend along the direction of water flow. ∑18PAHs predominantly consisted of low molecular weight PAHs. The principal component analysis and isomer ratios of PAHs suggested the mixed sources of petroleum and those from the combustion of petroleum, coal, and biomass. The results showed that the PAHs in the sediments of the Lanzhou Reach of the Yellow River have a low ecological risk. However, the BaP equivalent exposure values suggested a potential cancer risk.

Transcriptomic analysis of the mechanisms of alleviating renal interstitial fibrosis using the traditional Chinese medicine Kangxianling in a rat model.

Renal interstitial fibrosis (RIF) is currently recognized as a crucial mechanism of the pathogenesis of chronic kidney disease (CKD). Kangxianling (KXL, anti-fibrin) is a traditional Chinese medicine that has been proven to significantly reduce the levels of ECM deposition and inhibit renal fibrosis. To characterize the mechanisms and drug targets of KXL, we established a RIF rat model and treated the rats with KXL and losartan. Histological analyses validated the establishment of the RIF model and the treatment effect of KXL. Multiple levels of transcriptomic datasets were generated using lncRNA, mRNA and microRNA sequencing of kidney tissues. Functional annotations and pathway analyses were performed to unravel the therapeutic mechanisms. A multi-level transcriptomic regulatory network was built to illustrate the core factors in fibrosis pathogenesis and therapeutic regulation. KXL and losartan significantly reduced the progression of RIF, and a better therapeutic effect was shown with higher concentrations of KXL. According to the cluster analysis results of the RNA-seq data, the normal control (NC) and high concentration of KXL (HK) treatment groups were the closest in terms of differentially expressed genes. The WNT, TGF-ß and MAPK pathways were enriched and dominated the pathogenesis and therapy of RIF. miR-15b, miR-21, and miR-6216 were upregulated and miR-107 was downregulated in the fibrosis model. These small RNAs were shown to play critical roles in the regulation of the above fibrosis-related genes and could be inhibited by KXL treatment. Finally, based on the lncRNA datasets, we constructed a mRNA-lncRNA-miRNA coexpression ceRNA network, which identified key regulatory factors in the pathogenesis of kidney fibrosis and therapeutic mechanisms of KXL. Our work revealed the potential mechanism of the Chinese medicine Kangxianling in inhibiting renal interstitial fibrosis and supported the clinical use of KXL in the treatment of kidney fibrosis.

Biotechnological Management of Angiopathic Wounds: Challenges and Perspectives.

Angiopathic wound is a wound that develops as a result of a local vascular lesion. Angiogenesis is an important aspect underlying repair, and increased angiogenesis could accelerate and improve the healing outcome. Biotherapy has been used more and more in clinic and brings hope for angiopathic wound treatment, through the rapid recovery of angiogenesis and regulation and correction of the whole wound microenvironment. In this article, we discuss the advantages and disadvantages of various technologies ranging from presentation of angiogenic growth factors, genetic strategies, stem cells, and biomaterials engineering in angiopathic wound treatment.

Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF-ß/TßR and Imp7/8.

Compound Astragalus and Salvia miltiorrhiza extract (CASE) is a Chinese herbal formula consisting of astragalosides, astragalus polysaccharide and salvianolic acids extracted from Astragalus membranaceus and Salvia miltiorhiza. Previous studies by our group have demonstrated that CASE effectively suppresses diethylinitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats via modulating transforming growth factor ß/Mothers against decapentaplegic (TGFß/Smad) signaling. To further elucidate the mechanism of CASE, the effects of CASE on TGF-ß1, the serine/threonine kinase receptors of TGF-ß [TGF-ß receptor type-I (TßRI) and TßRII] and karyopherins [Importin 7 (Imp7) and Imp8], which are crucial for TGF-ß/Smad signaling in fibro-hepatocarcinogenesis, were assessed in the present study using in vivo (DEN-induced HCC in rats) and in vitro [TGF-ß1-stimulated rat myofibroblasts (MFBs) and HepG2 cells] models of fibro-hepatocarcinogenesis. Hematoxylin and eosin staining revealed that CASE may suppress inflammatory reactions and fibrosis in HCC as well as increasing the differentiation of HCC cells. Positive TGF-ß1 staining was increased in HCC nodule areas and in adjacent normal liver tissues in DEN-treated rats, while TßRI staining was increased only in normal adjacent liver tissues. The elevated expression of TGF-ß1, TßRI and TßRII was suppressed by CASE. CASE treatment also reduced glutathione S-transferase P 1 and Imp7/8 protein expression in fibro-hepatocarcinogenesis. In vitro experiments confirmed that CASE was able to decrease the expression of TßRI and TßRII in TGF-ß1-stimulated MFBs and HepG2 cells. These results indicate that the anti-HCC effect of CASE may be achieved by mediating TGF-ß/TßR and Imp7/8 protein expression, suggesting that CASE has multiple targets in HCC treatment.

Compound Astragalus and Salvia miltiorrhiza extracts modulate MAPK-regulated TGF-ß/Smad signaling in hepatocellular carcinoma by multi-target mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorrhiza Bunge (Lamiaceae) are two important Chinese herbs with a long history of extensive ethnobotanical usage in the treatment of liver-related diseases over many centuries. Presently, these two herbs are being used either as a single herbal formulation or a composite formula for the treatment of liver related conditions. In response, recent studies on these two herbs have focused on elucidating their mechanisms of action, particularly with regards to their anti-hepatocarcinogenic effects. Previously, we have reported that Compound Astragalus and Salvia miltiorrhiza extract (CASE), a synergized composite extract from Astragalus membranaceus and Salvia miltiorrhiza ameliorates liver fibrosis and hepatocellular carcinoma (HCC) by modulating the TGF-ß/Smad pathway. Meanwhile, MAPK activation and MAPK-dependent linker phosphorylation of Smad2/3 and their preferential nuclear import are crucial for overall oncogenic role of TGF-ß/Smad signaling in HCC. To elucidate further, we studied the effect of CASE on the MAPK pathway and how it affects MAPK-dependent regulation of TGF-ß/Smad signaling using both cell and animal models of HCC. MATERIALS AND METHODS: We used immunofluorescence and western blot techniques to monitor effect of CASE on the activation of the MAPKs (pERK, pJNK and pp38) in TGF-ß1-stimulated hepatic stellate cells (HSCs), HepG2 cells and also diethylnitrosamine (DEN)-induced HCC in rats. Also phosphorylation and subcellular distribution of pSmad2/3, Smad4 and Imp7/8 in TGF-ß1-stimulated HSC and HepG2 cells were monitored. The expression of pERK, pJNK, pp38 and PAI-1 gene were monitored by using western blot technique. The effect of CASE on domain-specific phosphorylation of Smad2/3 and their subcellular distribution, and the expression of Smad4 and its subcellular distribution in TGF-ß1-stimulated HSCs and HepG2 cells were evaluated by using immunofluorescence technique. And the expression of Imp7/8 and their subcellular distribution were assessed by both immunofluorescence and western blot techniques, while PAI-1 gene expression was assessed by western blot RESULTS: In vitro, CASE in a concentration-dependent manner increased the expression of pp38 but decreased the expression of pERK and pJNK; however, in vivo, CASE in a dose dependent manner decreased the expression of pERK, pJNK as well as pp38. Also, CASE concentration dependently inhibited pSmad2C/L, pSmad3L, Smad4, Imp7/8 and their nuclear import; it had no effect on pSmad3C in HepG2 cells; significantly decreased PAI-1 gene expression in both in vitro and in vivo. CONCLUSIONS: CASE blocked MAPK activation, MAPK-dependent linker phosphorylation of Smad2/3, Smad4 expression, Imp7 expression and their nuclear import leading to significant down-regulation of PAI-1 gene expression; further highlighting the multi-target anti-HCC effect of CASE and its potential drug candidature.

Antioxidant effect of salvianolic acid B on hippocampal CA1 neurons in mice with cerebral ischemia and reperfusion injury.

OBJETIVE: To investigate the neuroprotective effects and underlying mechanisms of salvianolic acid B (Sal B) extracted from Salvia miltiorrhiza on hippocampal CA1 neurons in mice with cerebral ischemia reperfusion injury. METHODS: Forty male National Institute of Health (NIH) mice were randomly divided into 4 groups with 10 animals each, including the sham group, the model group, the SalB group (SalB 22.5 mg/kg) and the nimodipine (Nim) group (Nim 1 mg/kg). A mouse model of cerebral ischemia and reperfusion injury was established by bilateral carotid artery occlusion for 30 min followed by 24-h reperfusion. The malondialdehyde (MDA) content, the nitric oxide synthase (NOS) activity, the superoxide dismutase (SOD) activity and total antioxidant capability (T-AOC) of the pallium were determined by biochemistry methods. The morphologic changes and Bcl-2 and Bax protein expression in hippocampal CA1 neurons were observed by using hematoxylineosin staining and immunohistochemistry staining, respectively. RESULTS: In the SalB group, the MDA content and the NOS activity of the pallium in cerebral ischemia-reperfusion mice significantly decreased and the SOD activity and the T-AOC significantly increased, as compared with the model group (P<0.05 or P<0.01). The SalB treatment also rescued neuronal loss (P<0.01) in the hippocampal CA1 region, strongly promoted Bcl-2 protein expression (P<0.01) and inhibited Bax protein expression (P<0.05). CONCLUSIONS: SalB increases the level of antioxidant substances and decreases free radicals production. Moreover, it also improves Bcl-2 expression and reduces Bax expression. SalB may exert the neuroprotective effect through mitochondria-dependent pathway on hippocampal CA1 neurons in mice with cerebral ischemia and reperfusion injury and suggested that SalB represents a promising candidate for the prevention and treatment of ischemic cerebrovascular disease.

Compound Astragalus and Salvia miltiorrhiza extract suppresses rabbits' hypertrophic scar by modulating the TGF-ß/Smad signal.

BACKGROUND: Hypertrophic scar is a fibro-proliferative disease. Our previous studies demonstrate that compound Astragalus and Salvia miltiorrhiza extract (CASE) inhibits proliferation and invasion in keloid fibroblasts. OBJECTIVE: To investigate the effects of CASE on hypertrophic scar. METHODS: Rabbits were divided into the control, model and three dosage groups of CASE (0.94, 1.88, 3.76%). An animal model of hypertrophic scar was established and treated with CASE ointment or ointment base. The histopathological detection by hematoxylin & eosin and Masson's trichrome staining and protein expression of scars by Western blot were performed. RESULTS: The hydroxyproline content was decreased under CASE treatment. Transforming growth factor beta 1 (TGF-ß1) protein expression increased in the model group while it decreased under CASE treatment. The elevated expression of Smad4 protein was decreased under CASE treatment. Additionally, CASE promoted Smad7 protein expression. CONCLUSION: CASE could inhibit formation of hypertrophic scar by modulating TGF-ß/Smad signal and may be useful for the treatment of hyperplastic scars.

[Effects of salvianolic acid B on cerebral energy charge and activity of ATPase in mice with cerebral ischemia].

OBJECTIVE: To observe the effect of salvianolic acid B (SalB) on high energy phosphate and activity of ATPase of cerebral ischemia in mice, and to study the role of SalB on hydrocephalus further. METHOD: NIH mice were divided into four groups randomly: Sham-operated group, cerebral ischemia group, SalB-treated group and Nimodipine (Nim)-collated group. In Sal B-treated group, mice were injected with SalB (22.5 mg x kg(-1)) in vena caudalis at 30 min before the experiment. In Nim-collated group, Nim (0.03 mg x kg(-1)) was injected into tail vein at the same time, while the mice in Sham-operated group and cerebral ischemia group were injected the same volume normal saline. The acute cerebral ischemia model was established by ligating bilateral common carotid arteries for 30 min in mice, then the mice were killed and the content of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), phosphocreatine (PCr) were observed, and the cerebral energy charge (EC) was computed. At the same time, activity of Na(+) -K(+) -ATPase and Ca2(+) -ATPase, content of water in brain tissue were measured. RESULT: Compared with cerebral ischemia group, EC and content of ATP, ADP, PCr in SalB-treated group heightened evidently (P < 0.01). Moreover, activity of Na(+)-K+ ATPase and Ca2+ ATPase in SalB-treated group had a remarkable increase (P < 0.01). But the content of water in brain tissue decreased markedly (P < 0.05). CONCLUSION: The mechanism that SalB can relieve content of water in brain tissue of cerebral ischemia in mice, may be associated with improving the content of high-energy phosphoric acid compounds and enhancing the activity of ATPase.

[Effect of salvianolic acid B on brain energy metabolism and hydrocephalus of cerebral ischemia in mice at different time].

Mice pathological model of acute cerebral ischemia was established. In order to observe the effect of salvianolic acid B (Sal B) on brain energy metabolism and hydrocephalus in the brain of mice at different ischemic times, the energy charge (EC), content of phosphocreatine (PCr), level of lactic acid (Lac), activity of Na+ -K+ -ATPase, brain index and water content of brain were measured at 6, 12, 18, 24, and 30 min, separately after ligating bilateral common carotid arteries in mice. NIH mice were randomly divided into sham-operated group (sham), cerebral ischemia group (ischemia), Sal B-treated group (Sal B) and nimodipine-collated group (Nim). At 6 min after cerebral ischemia, EC, content of PCr and activity of Na +-K -ATPase began to decrease, while level of Lac, brain index and water content of brain increased gradually. However, Sal B (22.5 mg x kg(-1) improved pathophysiological changes at different ischemic times. Especially at 30 min after cerebral ischemia in Sal B group, EC (P < 0.01), content of PCr (P < 0.01 and activity of Na+ -K+ -ATPase ( < 0.05) increased significantly. Meanwhile, level of Lac (P < 0.01, brain index (P < 0.01) and water content of brain (P < 0.05) were lower obviously than those of cerebral ischemia group. Sal B could alleviate hydrocephalus by the improvement of energy metabolism in mice with acute cerebral ischemia, that provides scientific evidence that Sal B can be used for the clinical application of ischemic diseases.

[Effects of naoreqing on secretive function of vaso-endothelial cells in rabbits with endotoxic fever].

OBJECTIVE: To observe the antifebrile effect of Naoreqing (NRQ) oral liquid on secretive function of vaso-endothelial cells in rabbits with endotoxic fever. METHODS: Endotoxic fever rabbit model was duplicated to observe the effects of NRQ on body temperature, blood levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and endothelin (ET) using radioimmunoassay, as well as activity of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in plasma by chromophoric substrate assay. RESULTS: Comparisons of various indexes between the two groups showed significantly difference, i.e. the maximal increment of body temperature: 0.69 +/- 0.07 degrees C vs 1.31 +/- 0.13 degrees C (the NRQ treated group vs the untreated model group, the same hereafter); 2h thermal response index TRI2 4.85 +/- 0.57 vs 8.44 +/- 0.98; plasma ET content 197.96 +/- 39.11 ng/L vs 250.80 +/- 40.99 ng/L; TXB2 content 177.35 +/- 77.30 ng/L vs 279.64 +/- 83.74 ng/L; activity of PAI 0.84 +/- 0.01AU/ml vs 0.86 +/- 0.01 AU/ml; plasma 6-keto-PGF1alpha content 986.70 +/- 327.36 ng/L vs 507.81 +/- 170.01 ng/L; activity of t-PA 0.25 +/- 0.02 IU/ml vs 0.21 +/- 0.02 IU/ml (P < 0.05, P < 0.01). CONCLUSION: NRQ may improve secretive function of vaso-endothelial cells to dilate blood vessel and quicken heat dissipation through body surface, so as to play an integral antipyretic effect in rabbits with endotoxic fever.

[Protective effect of jasminoidin on cascade of damage of cerebral ischemia in rats].

OBJECTIVE: To study the protective effect of jasminoidin on cascade of damage of cerebral ischemia. METHOD: The rats were randomly divided into four groups: sham-operated group, ischemic group, the jasminoidin-treatment group and PNS-treatment group. Focal cerebral ischemia was produced by permanent occlusion of left middle cerebral artery (PMCAO) in rats. Radioimmunoassay (RIA) was utilized to identify the content of tumor necrosis factor-alpha (TNF-alpha) and interlukin 1beta (IL-1beta) in brain tissue of rats following ischemia. and that of Neuron-specific enolase (NSE) in rat's serum was observed too. The plasma concentration of vonWillebrand factor (vWF) was identified by enzyme-linked immunoadsordent assay (ELISA). RESULT: After 12 h and 24 h of ischemia, the contents of TNF-alpha and IL-1beta and vWF as well as on NSE showed concomitant increase. Jasminoidin dramatically inhibited the increase of TNF-alpha and IL-1beta after 12 h and 24 h of ischemia, and repressed the increase of vWF after 12 h and 24 h of ischemia too. However, the influence of jasminodin NSE after 12 h and 24 h of ischemia was not significant. CONCLUSION: Jasminoidin had good effect on repressing the expression of TNF-alpha and IL-1beta as well as vWF caused by cerebral ischemia, thus it manifested the effect of relieving the damage to vascular endothelial cell and blocking the progress of cascade damage of cerebral ischemia through inhibiting the process of inflammation.