Supported by the Guangxi Science and Technology Infrastructure Construction Project of China (09-007-06).

1 Introduction

Mangiferin (MGF) is a chemical compound found in Mango or Anemarrhena, and studies have shown that it has anti-inflammatory effects[1]. Hypertension is a low-grade inflammation state of the disease[2-3], and easily complicated by the heart, brain, kidneys and other organs’ inflammatory response[4]. However, there are few studies on MGF anti-hypertensive inflammatory injury. In the previous research, we found that MGF had a protective effect on the heart, brain and kidney’s morphological injury induced by hypertension in spontaneously hypertensive rats (SHRs)[5]. In this experiment, we will further reveal the mechanism of MGF protection on heart, brain and kidneys’ inflammatory injury in SHRs through observing the effects of MGF on Inflammatory factors including TNF-α, iNOS, ICAM-1 and its mRNA expression in heart, brain and kidneys. It is expected to provide an experimental basis for finding a new drug to reduce hypertensive target organs’ inflammatory injury.

散步是最适合孕妈妈的一项运动，妊娠各个阶段都可以进行。散步不仅能加强心肺等脏器的功能，还可以促进新陈代谢，加强腿部肌肉、腹壁肌肉的力量，是一种有效的锻炼方法，有利于顺利分娩。

2 Materials and methods

2.1 Materials

教学问题意识是另一个重要的内在因素．事实上，那些没有教学问题意识，或者教学问题意识薄弱的职前教师，他们在“空气质量问题”的教学设计中，大多缺少对知识的“发问”和“追问”，更难以透过教学现象认清教学本质．然而，那些具有教学问题意识的职前教师，他们不仅善于思考教学中的诸多问题，譬如如何设置情境以引入知识，如何通过问题的设计突出重点、突破难点，如何合理地安排各个教学环节等，而且善于寻求对教学问题的解决方法．

2.1.1 Animals. In the experiment, 40 ten-week-old male SHRs and 8 ten-week-old male normotensive Wistar-Kyoto (WKY) rats were used. The weight was in the range of 280-320 g (License No. SCXK 2006-0009), and they were obtained from Beijing Vital River Lab Animal Technology Co., Ltd. These rats were randomly divided into the model group, the high-dose, medium-dose, low-dose MGF groups and the Benazepril group, with 8 rats in each group. The WKY rats were used for the normal control group. The experiment was carried out in accordance with the internationally accepted principles for laboratory animal use and care as found in the European Community guidelines (EECDirectiveof 1986; 86/609/EEC), and the animals were kept under controlled conditions of temperature, humidity and light, with free access to food and water available in the whole stages of the experiment.

In each 100 mg tissue, added 1 mL of RIPA and 10 μL of 100 mM phenylmethylsulfonyl fluoride (PMSF) and 10 μL of phosphatase inhibitors (not previously added to RIPA, otherwise the performance of PMSF would lose). Homogenized, avoid foaming and heating, the samples were transferred to 1.5 mL tubes, ice placed 30 min, and used 1.5 mL tubes containing samples, centrifuged at the speed of 12 000 g/min at 4℃ for 30 min. Carefully transferred the supernatant to a clean sterile centrifuge tube, and stored at -20℃.

秦安县水土流失严重，生态环境恶劣，干旱缺水是制约经济和社会发展的最大瓶颈。建立一个合理高效的生态系统，以可持续发展为目标，通过加大花椒产业基础设施建设投入，引进先进花椒品种及栽培技术。增建节水灌溉设施、增施有机肥、改善土壤理化性状等耕作技术，调整当地种植结构，建立科学合理的耕作制度，推广地膜覆盖、设施栽培技术，充分利用天然降雨，减少地下水的使用，制定立体高效生态林果业等一系列措施，控制生态系统的恶化，实现环境、经济和社会的可持续发展。

4.7 Effects of MGF on the expression of TNF-α, iNOS and ICAM-1 mRNA in the kidney of SHRs Compared with the control group, the expression of TNF-α, iNOS and ICAM-1 mRNA in the model group was significantly increased (P<0.01); compared with the model group, the expression of TNF-α, iNOS and ICAM-1 mRNA in the Benazepril group was significantly decreased (P<0.01), and that of each dose MGF group was significantly decreased (P<0.01); among the intervention groups, the expression of iNOS mRNA in the high-dose MGF group was lower than that of the Benazepril group (P<0.05)(Fig.6).

2.2 Methods

2.2.1 Drug treatment. MGF was dissolved in heated distilled water, dissolved into desired concentration, respectively 4, 2, 1 g/L. The rats in the MGF groups were treated with a high, medium and low dose of MGF[40, 20, 10 mg/(kg·d), respectively, intragastrically (ig)]; Benazepril[10 mg/(kg·d), ig]was administered in the benazepril group; triple-distilled water was applied to the rats in the normal control group and the model group, all rats were treated for 8 weeks consecutively[10 mL/(kg·d), ig].

2.2.2 Blood pressure measurement. We used non-invasive blood pressure instruments to measure the systolic blood pressure in the rats’ tail artery. Before taking measurements, the rats were placed in a 35℃ incubator to warm up for 10 minutes to dilate the vessels, then pressure was measured, took 4 to 6 measurements, then took the average.

The data was analyzed using SPSS11.0, and was presented as mean ± standard deviation. The significance of the difference between multiple means was determined by the single factor analysis of variance. Probability values of P<0.05 denote significant difference.

2.2.4 Tissue preparation for western blot. The tissues were rapidly frozen in tissue wells, then placed directly on dry ice, and stored at -80℃.

2.1.2 Main reagents and drugs. CCR2 antibody (ab 21667), MCP-1 antibody (ab7202) from Abcam, SDS-PAGE gel preparation kit from Biyuntian, RIPA (R0095) protein extracts from Shanghai Shenneng Bocai Biological Technology Co., Ltd. RNA enzyme A (RNAse A) from Sigma; Trizol (15596-026) reagent extracts from Invitrogen, reverse transcription kit (MBI 00032062) from the Revert Aid RTTMFISRt, TNF-α, iNOS and ICAM-1 mRNA primers from Shanghai Sangon.

2.2.5 Tissue preparation for RT-PCR. The tissues were cut into pieces (maximum area should be not greater than 0.5 cm), and 1 mL Trizol was added to the sample, then placed into a 4℃ refrigerator overnight and then moved to a -80℃ refrigerator.

2.2.6 Western blot procedure. First, 20 μL of tissue lysate was used and added 5 μL 5 × electrophoresis sample buffer (took pre-stained Maker 5 μL), put in the boiling water bath for 5 min, centrifuged at 12 000 g/min for 3 min, removed insoluble proteins, samples were loaded and separated by electrophoresis (5% stacking gel 90V, 12% separating gel 110V, not constant current) about 1.5 h. Took separated glue transfer film (the electric meter wiped film, 90V 30 min). Turned on the electroporation instrument, removed the nitrocellulose membrane washed with deionized water, lotion equilibrated with 5% skim milk (diluted with PBS or TBS) blocking at room temperature for 30 min, then 4℃ overnight, balanced in the next day at room temperature. Added diluted mouse anti-TNF (1∶1 000), rabbit anti-iNOS (1∶2 000) and mouse anti-ICAM-1(1∶2 000) (diluted solution containing 2% skim milk), placed at 4℃ overnight. Then, washed the membrane with PBS (or TBS), the first 15 min, then each of the three 5 min. Added 5 mL of 1∶5 000 dilution (diluted solution containing 2% skim milk powder) of goat anti-mouse or goat anti-rabbit secondary antibody, reacted at 37℃ for 1 h. And after washing thoroughly, dried, exposed to Kodak XAR5 film (Sigma), and exposed at -70℃. Used WD-9413B gel imaging system and software to analyze the film Gelpro32 of protein bands of gray value.

Relative expression level = A target gene/Aβ-actin gene.

The primers and their sequences are shown in Table 1 and the primers’ PCR cycle parameters are shown in Table 2.

影响主要包括两个方面，一是准确度，主要指空间精度、时间精度和专题性精度。以空间精度为例，其空间特性如何正确度量，应该以空间维度作为衡量标准，如何确定标准，目前存在一定争议。二是精确度，分为空间分辨率和细度。空间分辨率的有效应用，能够对地面物体进行准确分辨，其定义也可以通过地图比例中所明确的最小比例值来加以显示。精准度存在问题，则会直接对数据库具体应用项目是否适用产生一定影响，需要保证分辨率充分满足数据细节使用需要。

Table 1 Primers and their sequences

PrimersPrimersequences TNF⁃αSensePrimer：5′⁃TTGACCTCAGCGCTGAGTTG⁃3AntisensePrimer：5′⁃CCTGTAGCCCACGTCGTAGC⁃3′iNOSSensePrimer：5′⁃AGCTCCTCCCAGGACCACAC⁃3′AntisensePrimer：5′⁃ACGCTGAGTACCTCATTGGC⁃3′ICAM⁃1SensePrimer：5′⁃AAACGACGCTTCTTTTGCTC⁃3′AntisensePrimer：5′⁃GGTGTTCCTTTTCTTCTCTTGCT⁃3′β⁃actinSensePrimer：5′⁃TGGAATCCTGTGGCATCCATGAAAC⁃3AntisensePrimer：5′⁃TAAAACGCAGCTCAGTAACAGTCCG⁃3

Table 2 Primers’ PCR cycle parameters

NumberofcyclesTemperature∥℃TimeProcess1953minPreparatorydenaturation359430secDenaturation355630secAnnealing35721．5minExtending1728minHeatpreservation4Preservation

3 Statistical analysis

2.2.3 Tissue collection. Fasting 12 hours after the last administration of drugs, the rats were anesthetized intra-abdominally with chloral hydrate (0.3 mg/kg). Firstly, an incision was made in the abdomen to expose the kidneys which were removed and saline washed. The heart was removed and saline washed. Lastly, the skull was opened and the brain was removed.

4 Results

4.1 Effects of MGF on blood pressure levels of the SHRs Before intragastric administration, compared with the normal control group, the model group’s blood pressure level was significantly increased (P<0.01). After intragastric administration for 4 and 8 weeks, compared with the normal control group, the model group’s BP level was significantly increased (P<0.01); compared with the model group, the benazepril group’s BP level was significantly decreased (P<0.01). Each dose MGF group’s BP level was slightly decreased, but were not statistically different (P>0.05); among the intervention groups, each dose MGF group’s BP level was significantly higher than that of the benazepril group (P<0.01), shown in Table 3.

Table 3 Comparison of blood pressure levels among groups before and after 4 and 8 weeks of intervention±s, n=8, mmHg)

GroupBpbeforeinterventionBpafter4weeksofinterventionBpafter8weeksofinterventionNormalcontrol113．05±2．34112．36±3．45114．33±6．58Model162．43±30．55174．39±31．33∗∗187．59±37．77∗∗Benazepril164．37±32．34147．36±23．35●●155．25±34．54●●High⁃doseMGF163．38±31．28170．21±29．50ΔΔ181．21±34．40ΔΔMedium⁃doseMGF162．56±30．36171．26±30．40ΔΔ183．26±32．60ΔΔLow⁃doseMGF165．49±29．38172．45±32．78ΔΔ184．45±33．58ΔΔ

Note: **P<0.01, compared with the normal control group; ●●P<0.01, compared with the model group; ΔΔP<0.01, compared with the Benazepril group.

4.2 Effects of MGF on the expression of TNF-α, iNOS and ICAM-1 in the heart of SHRs Compared with the normal control group, the expression of TNF-α, iNOS and ICAM-1 in the model group was significantly increased (P<0.01); compared with the model group, the expression of TNF-α, iNOS and ICAM-1 in the Benazepril group was significantly decreased (P<0.05 or P<0.01), and that of each dose MGF group was significantly decreased (P<0.05 or P<0.01) (Fig.1).

2.2.4 不同处理下整个生长季的草地总载畜量 整个生长季的草地总载畜量DM总载畜量最高，其次为ME总载畜量，DCP总载畜量最低。施肥和补播处理下草地DM总载畜量(246.81和239.80羊单位/hm2)分别比CK增长33%和30%，DCP总载畜量(133.50和124.89羊单位/hm2)分别比CK提高20%和12%，ME总载畜量(210.83和213.22羊单位/hm2)仅比CK高0.2%和1%。说明施肥和补播对DM载畜量的促进作用最明显，对DCP载畜量次之，对ME载畜量无明显促进作用。

Notes: A: Electrophoresis. a: Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group; B: **P<0.01, compared with the normal control group; ●P<0.05, ●●P<0.01, compared with the model group.

Fig.1 Comparison of the expression of TNF-α, iNOS and ICAM-1 in the heart of SHRs among different groups

4.3 Effects of MGF on the expression of TNF-α, iNOS and ICAM-1 in the brain of SHRs Compared with the normal control group, the expression of TNF-α, iNOS and ICAM-1 in the model group was increased (P<0.05 or P<0.01); compared with the model group, the expression of iNOS in the Benazepril group was decreased (P<0.05), the expression of TNF-α, iNOS in medium and low dose MGF group was decreased (P<0.05), compared with the Benazepril group, the expression of iNOS in low-dose MGF group was decreased (P<0.05) (Fig.2).

4.4 Effects of MGF on the Expression of TNF-α, iNOS and ICAM-1 in the Kidney of SHR Compared with the normal control group, the expression of TNF-α in the model group was increased (P<0.05); compared with the model group, the expression of TNF-α in the medium-dose MGF group was decreased (P<0.05), the expression of iNOS in the low-dose MGF group was decreased (P<0.05) (Fig.3).

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Notes: A: Electrophoresis. a:Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group; B: *P<0.05, **P<0.01, compared with the normal control group; ●P<0.05, compared with the model group; ΔP<0.05,compared with the Benazepril group.

Fig.2 Comparison of the expression of TNF-α, iNOS and ICAM-1 in the brain of SHRs among different groups

Notes: A: Electrophoresis. a:Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group. B: *P<0.05,compared with the normal control group; ●P<0.05, compared with the model group.

Fig.3 Comparison of the expression of TNF-α, iNOS and ICAM-1 in the kidney of SHRs among different groups

4.5 Effects of MGF on the expression of TNF-α, iNOS and ICAM-1 mRNA in the heart of SHRs Compared with the normal control group, the expression of TNF-α, iNOS and ICAM-1 mRNA in the model group was significantly increased (P<0.01);compared with the model group, the expression of TNF-α, iNOS and ICAM-1 mRNA in the Benazepril group was significantly decreased (P<0.05 or P<0.01), that of each dose MGF group was significantly decreased (P<0.01); Among the intervention groups, the expression of TNF-α mRNA in the medium-dose and low-dose MGF group was higher than that of Benazepril group (P<0.05 or P<0.01), the expression of iNOS mRNA in the high-dose and medium-dose MGF group was lower than that of the Benazepril group (P<0.05 or P<0.01) (Fig.4).

Notes: A: Electrophoresis. a:Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group. B: **P<0.01,compared with the normal control group; ●P<0.05, ●●P<0.01, compared with the model group; ΔP<0.05, ΔΔP<0.01, compared with the benazepril group.

Fig.4 Comparison of the expression of TNF-α, iNOS and ICAM-1 mRNA in the heart of SHRs among different groups

4.6 Effects of MGF on the expression of TNF-α, iNOS and ICAM-1 mRNA in the brain of SHRs Compared with the control group, the expression of TNF-α and ICAM-1 mRNA in the model group was significantly increased (P<0.05 or P<0.01); compared with the model group, the expression of TNF-α and ICAM-1 mRNA in benazepril group was significantly decreased (P<0.05 or P<0.01), that of each dose MGF group was significantly decreased (P<0.01), the expression of iNOS mRNA in the high-dose and medium-dose MGF group was significantly decreased (P<0.01); Among the intervention groups, the expression of iNOS mRNA in the high-dose MGF group was lower than that of the Benazepril group (P<0.05)(Fig.5).

MGF (formula: C19H18O11, mango leaves extract, 98% purity, batch number: 20150603), from Guangxi Key Laboratory of Efficacy Study on Chinese Medicine; Benazepril (batch number: X1564), from Beijing Novartis Pharmaceutical Co., Ltd.

Notes: A: Electrophoresis. a:Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group. B: *P<0.05, **P<0.01, compared with the normal control group; ●P<0.05, ●●P<0.01, compared with the model group; ΔP<0.05,compared with the benazepril group.

Fig.5 Comparison of the expression of TNF-α, iNOS and ICAM-1 mRNA in the brain of SHRs among different groups

2.2.7 RT-PCR procedure. Total RNA extraction, identification, reverse transcriptase in the PCR instrument, PCR reaction, results observation in gel electrophoresis imaging analyzer. All gel electrophoresis results were analyzed with Quantity One 4.6.2 software, the average A of each group was calculated, used the ratio of gene A and the corresponding β-actin as the mRNA relative expression level.

Notes: A: Electrophoresis. a:Normal control group; b: Model group; c: Benazepril group; d: High-dose MGF group; e: Medium-dose MGF group; f: Low-dose MGF group. B: **P<0.01,compared with the normal control group; ●●P<0.01, compared with the model group; ΔP<0.05,compared with the benazepril group.

Fig.6 Comparison of the expression of TNF-α, iNOS and ICAM-1 mRNA in the kidney of SHRs among different groups

5 Conclusions and discussions

5.1 Conclusions MGF had no significant lowering BP effect, SHR showed inflammatory injury in the heart, brain and kidneys, MGF showed improvement on the inflammatory injury, the anti-inflammation mechanism may be associated with lowering TNF-α, iNOS and ICAM-1 and its mRNA expression.

5.2 Discussions Hypertension is a common cardiovascular disease[6].Hypertension has a high incidence of important risk factors for cardiovascular diseases, it can cause heart, brain and kidney damage, the treatment for hypertension must attach great importance to the protection of the heart, brain, kidney[7-9]. In recent years, the effect of inflammation in the occurrence and development of hypertension has attracted the attention of more and more scholars[10].

在语言教学结束时，教师会进行总结。这时，教师也可运用留白艺术，让幼儿进行总结，更进一步掌握本节所学的知识。

SHR model is the model closest to the genetic background of human essential hypertension, can increase blood pressure level spontaneously, so it is widely used in the study of medical research[11]. The heart, brain and kidneys of SHR have significant inflammatory injury[12].

TNF-α plays an important role in the regulation of neuroendocrine, vascular endothelial injury, vascular wall inflammation, smooth muscle cell proliferation and vascular remodeling, it may be involved in the pathological process of essential hypertension’s occurrence and development[13]. ICAM-1 belongs to a member of the immunoglobulin superfamily, it is a transmembrane single-chain glycoprotein, and it was reported that ICAM-1 expression level was significantly increased in hypertensive rats[14]. Under normal physiological conditions, iNOS has no expression generally, but in the pathological state, endotoxin and various cytokines can induce the expression of iNOS gene in macrophage and leukocyte, lead to a lot of NO production to inhibit the effect of endotoxin and various cytokines, and also cause strong blood pressure lowering effect[15].

The study found: compared with the normal control group, the model group’s BP level was significantly increased, before and after 4 and 8 weeks of gavage, blood pressure was continuously increasing, and the trend of changes in blood pressure was consistent with the results in the past report[16]. However MGF had no significant lowering BP effect. Additionally, compared with the normal control group, the expression of TNF-α, iNOS, ICAM-1 mRNA in model group was significantly increased, this showed that hypertension rats had inflammatory injury in target organs, this was consistent with the results reported by Sun etal[12].MGF could reduce the level of expression of these inflammatory cytokines, it showed that MGF could reduce inflammation response, thereby protected the target organs, which was consistent with the results that MGF can lower the inflammatory factors’ expression in the heart, brain and kidney reported in the past[17-19]. Benazepril is an antihypertensive drug commonly used in clinic[20], in the same time, it can inhibit the inflammatory response of the whole body or some organs[21-23]. This study found that between the benazepril group and each dose MGF group, there was no significant difference in most of the indicators.

最后，必须要定期的对学生进行阶段性考核，准确有效地了解学生的学习进展情况，然后依照学生的学习进展对教学目标不断的进行调整，以此来保证教学目标的适用性，进而保证高中化学分层教学模式能够有效地发挥出应有的作用。

在花卉种植过程中，施肥主要在每年新芽长出之前、发育期间进行，可以促进植株生长、保护土壤墒情，对于充分利用土地资源具有非常重要的意义。在施肥过程中需要合理控制氮磷钾肥的配比。对于花卉的灌溉，应根据花卉的生长情况及当地的雨水情况进行。对于降水量较多的情况，还应及时做好排水工作，以免导致花卉死亡［4］。

These results suggest that MGF had no significant lowering BP effect, SHRs showed inflammatory injury in the heart, brain and kidneys, MGF showed improvement in the injury of the organs, and the anti-inflammation mechanism may be associated with lowering TNF-α, iNOS, ICAM-1 and its mRNA expression. This also explained that lowering BP and anti-hypertensive inflammation are two independent pharmacological effects, and they are not positively correlated.

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