心房钠尿肽对脂多糖所致大鼠急性肺损伤的影响

目的:探讨心房钠尿肽(ANP)对脂多糖(LPS)血症大鼠急性肺损伤的作用和机制。方法: 大鼠静脉给予LPS(2 mg·kg^－1)后立即静脉给予ANP(2 μg·kg^－1),记录动物平均动脉血压(MAP)、检测血浆一氧化氮(NO)和内皮素(ET)浓度、测定肺水含量并做肺组织病理学检查。结果: 给予LPS的大鼠,MAP持续下降,至4 h MAP(8.1±2.6)kPa;血浆NO和ET浓度均显著升高(P<0.01 vs control);4 h肺湿干比(5.15±0.43),显著高于对照组(P<0.05);大鼠肺组织病理学检查呈现肺间质水肿。LPS＋ANP组大鼠MAP在给药初期的短暂下降后逐步回升,至4h MAP(13.4±2.9)kPa(P<0.05 vs LPS);4 h血浆NO水平和ET浓度均显著下降(P<0.05 vs LPS),但仍明显高于对照组(P<0.01 vs control);肺湿干比(4.57±0.35)与对照组没有显著差异;肺组织病理学改变较LPS组明显减轻。结论: ANP对LPS引起的急性肺损伤有治疗作用,能调节LPS引起的动脉血压的持续下降,上述作用可能与ANP拮抗ET的产生、降低NO的分泌有关。     

Enhanced regeneration of rabbit mandibular defects through a combined treatment of electrical stimulation and rhBMP-2 application

We evaluated the new bone regeneration of a rabbit mandibular defect using hBMSCs under electrical stimulation combined with rhBMP-2 in this study. An inner scaffold prepared by setting a collagen sponge with hBMSCs and hydrogel was placed into a polycaprolactone (PCL) outer box, and an electrical stimulation device was installed between the inner scaffold and the outer box. There were three experimental groups depending on electrical stimulation and application of rhBMP-2. The experimental group was divided into the following three groups. Group 1, in which rhBMP-2 (5 μg/defect) was added to hydrogel and electrical stimulation was not applied; Group 2, in which rhBMP-2 (5 μg/defect) was added as in Group 1 and electrical stimulation was applied; and Group 3, in which electrical stimulation was applied and rhBMP-2 (5 μg/defect) was injected directly into defect site. The delivered electrical stimulation was charge-balanced bi-phasic electric current pulses, and electrical stimulation was conducted for 7 days. The stimulation parameters of the bi-phasic electrical current set at an amplitude of 20 μA, a duration of 100 μs and a frequency of 100 Hz. Four weeks after surgery, new bone formation in each group was evaluated using radiography, histology, and micro-computed tomography (μCT). Groups 2 and 3 exhibited a significant increase in new bone formation compared to Group 1, while Group 3 showed the highest level of new bone regeneration. In a comparison between two groups, Group 2 showed a higher bone volume (BV) by 260 % (p < 0.01) compared with Group 1, and Group 3 showed a higher BV by 442 % (p < 0.01) compared with Group 1. The trend of the bone surface density (ratio of new bone to the real defect volume, BS/TV), trabecular number, and connectivity was identical to that of the BV. The total bone mineral density (BMD) of Groups 2 and 3 showed values higher by the ratios of 103 % (p < 0.01) and 107.5 % (p < 0.01) compared with Group 1, respectively. Part BMD for Groups 2 and 3 showed higher values by the ratios of 104.9 % (p < 0.01) and 122.4 % (p < 0.01) compared with Group 1, respectively. These results suggest that the combined treatment of electrical stimulation, hBMSCs, a collagen sponge, hydrogel, and rhBMP-2 was effective for bone regeneration of large-size mandibular defects. The application of rhBMP-2 with an injection following electrical stimulation demonstrated better efficiency as regards bone regeneration.     

Acute Lung Injury in Response to Intratracheal Instillation of Lipopolysaccharide in an Animal Model of Emphysema Induced by Elastase

The response of lungs with emphysema to an acute lung injury (ALI) remains unclear. This study compared the lung response to intratracheal instillation of lipopolysaccharide (LPS) in rats with and without emphysema. Twenty-four Wistar rats were randomized to four groups: control group (C-G), ALI group (ALI-G), emphysema group (E-G), emphysema and ALI group (E-ALI-G). Euthanasia and the following analysis were performed 24 h after ALI induction: lung histology, bronchoalveolar lavage (BAL), mRNA expression of inflammatory mediators, and blood gas measures. The histological analysis showed that animals of ALI-G (0.55 ± 0.15) and E-ALI-G (0.69 ± 0.08) had a higher ALI score compared to C-G (0.12 ± 0.04) and E-G (0.16 ± 0.04) (p < 0.05). The analysis of each component of the score demonstrated that ALI-G and E-ALI-G had greater alveolar and interstitial neutrophil infiltration, as well as greater amount of alveolar proteinaceous debris. Comparing the two groups that received LPS, there was a trend of higher ALI in the E-ALI-G, specially due to a higher neutrophil infiltration in the alveolar spaces and a higher septal thickening. Total cell count (E-G = 3.09 ± 0.83; ALI-G = 4.45 ± 1.9; E-ALI-G = 5.9 ± 2.1; C-G = 0.73 ± 0.37 × 10⁵) and neutrophil count (E-G = 0.69 ± 0.35; ALI-G = 2.53 ± 1.09; E-ALI-G = 3.86 ± 1.4; C-G = 0.09 ± 0.07 × 10⁵) in the BAL were higher in the groups E-G, ALI-G, and E-ALI-G when compared to C-G (p < 0.05). The IL-6, TNF-α, and CXCL2 mRNA expressions were higher in the animals that received LPS (ALI-G and E-ALI-G) compared to the C-G and E-G (p < 0.05). No statistically significant difference was observed in the BAL cellularity and in the expression of inflammatory mediators between the ALI-G and the E-ALI-G. The severity of ALI in response to intratracheal instillation of LPS did not show difference in rats with and without intratracheal-induced emphysema.     

The alpha-lipoic acid derivative DHLHZn: a new therapeutic agent for acute lung injury in vivo

Objective and design

An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action.

Material

Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(?) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn).

Treatment

Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(?) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration.

Methods

Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test.

Results

Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(?) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(?) group (p < 0.001).

Conclusions

Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.

     

Diet and Diet Combined with Chronic Aerobic Exercise Decreases Body Fat Mass and Alters Plasma and Adipose Tissue Inflammatory Markers in Obese Women

The purpose of this study was to investigate the effect of 6 months aerobic exercise and diet alone or in combination on markers of inflammation (MOI) in circulation and in adipose abdominal tissue (AT) in obese women. Thirty obese subjects were randomized into a 24-week intervention: (1) exercise (EX), (2) diet (DI), and (3) exercise and diet (EXD). Blood samples were collected at baseline, after 12 and 24 weeks. AT biopsies were obtained only at baseline and after 24 weeks. In the EXD and DI groups, the fat loss was after 12 weeks was ?13.74 and ?7.8 % (P?<?0.01) and after 24 weeks was ?21.82 and ?17 % (P?<?0.01) with no changes in the EX group. After 12 and 24 weeks, maximal oxygen consumption (VO_2max) was increased by 21.81–39.54 % (P?<?0.05) in the EXD group and 18.09–40.95 % in the EX group with no changes in the DI group. In the EXD and DI groups, circulating levels of tumor necrosis factor α and interleukin 6 were decreased after 24 weeks for both groups (P?<?0.01). No changes in the EX group. Homeostatic model assessment for insulin resistance decreased (P?<?0.05) only after 24 weeks in the EXD group. In AT biopsies, subjects in the EXD and DI groups exhibited a significant decrease in MO (P?<?0.01 for all). No changes in AT biopsies were found in the EX group. In conclusion, chronic aerobic exercise was found to have no effects on circulating and AT MOI despite an increased VO_2max. Rather important body composition modifications were found to have beneficial effects on circulating and AT MOI in these obese women.     

Analysis of the Gene Expression Profile of Curcumin-Treated Kidney on Endotoxin-Induced Renal Inflammation

Acute or chronic kidney inflammation is closely related to the progress of kidney diseases. Curcumin, a yellow pigment present in the rhizome of turmeric (Curcuma longa L. Zingiberaceae), was found to be a potential anti-inflammatory agent. The present study aimed to investigate the effects and explore the protective mechanism of curcumin on lipopolysaccharide (LPS)-induced kidney inflammation in mice using gene chip and pathological technology. Nine SPF Kunming mice (aged 6–8 weeks, weighing 20–25 g) were divided into three groups. Saline and LPS were injected intraperitoneally in a normal control group and a model group, respectively. Mice in the treatment group were first injected with curcumin (5 mg/kg) for 3 days before being injected with LPS (5 mg/kg). Kidney tissues were harvested at 6 h after treatment. Parts of kidney were fixed with 10 % formaldehyde for HE, Periodic acid-Schiff staining, and immunohistochemistry. Affymetrix gene chips (mouse 430 chip) were used to detect the renal gene expression profile, and the results were analyzed using bioinformatics methods. The renal gene expression profile showed that there are 148 Affy IDs (up-down group) whose levels of gene expression were increased after LPS stimulation and decreased by curcumin treatment and that there are 133 Affy IDs (down-up group) exhibiting the opposite trend. In the differentially expressed genes of the up-down group, 21 Gene Ontology (GO) genes were selected by screening function (P?≤?0.01). In the biological processes, most of the genes were found to be related to the genes of regulation of macrophage activation and macrophage activation-associated genes. In the cellular localization, there were four functional GO genes (P?≤?0.01); in the molecular structure, there were seven functional GO genes (P?≤?0.01). In the down-up group, there were functional GO genes (P?≤?0.01) and one functional GO gene (P?≤?0.01) in the biological process and the cellular localization, respectively. Macrophage infiltration could be observed as early as 6 h after LPS stimulation. Pretreatment with 5 mg/kg of curcumin significantly decreased the macrophage infiltration. At 6 h after LPS injection, significant decreased expression of M6PRBP-1 and NEDD-4 was observed in renal tissue. On the other hand, pretreatment with curcumin significantly increased renal M6PRBP-1 and NEDD-4 expression. In this study, we also found the signaling pathway and the possible target gene of the protective effects of curcumin on endotoxin-induced renal inflammation. The kidney gene expression profile in the inflammatory state was clarified by using gene chip technology. Furthermore, we confirmed that curcumin treatment can change the gene expression profile.     

Urinary trypsin inhibitor reduced neointimal hyperplasia induced by systemic inflammation after balloon injury in rabbits

Objectives

The aims of this study were to evaluate the effect of urinary trypsin inhibitor (UTI) on the regulation of inflammatory cytokines induced by lipopolysaccharide (LPS) and the reduction of neointimal formation in rabbits.

Methods and results

Rabbits subjected to iliac artery balloon injury were randomly divided into three groups: control group (balloon injury), LPS group (LPS + balloon injury) and UTI group (UTI + LPS + balloon injury). Systemic markers of inflammation (serum IL-1β and TNF-α levels measured by ELISA) were increased after LPS administration. Arterial nuclear factor-κB (NF-κB/p65) at 28 days after injury was 31.50 ± 7.08 % of total cells in controls and 73.50 ± 6.90 % in LPS group (P < 0.05). Morphometric analysis of the injured arteries at 28 days revealed significantly increased luminal stenosis (45.81 ± 5.31 vs 27.93 ± 2.85 %, P < 0.05) and neointima-to-media ratio (1.40 ± 0.15 vs 0.68 ± 0.12, P < 0.05) in LPS-treated animals compared with controls. This effect was reduced by UTI administration. Serum IL-1β and TNF-α levels and NF-κB/p65 expression were significantly increased in correlation with the severity of intimal hyperplasia and inhibited by UTI.

Conclusions

Systemic inflammatory response concurrently with arterial vascular injury facilitated neointimal formation. UTI reduced neointimal hyperplasia by regulating inflammatory response and could be considered as a potential anti-restenosis supplement.     

Overload training inhibits phagocytosis and ROS generation of peritoneal macrophages: role of IGF-1 and MGF

We tested the hypothesis that overload training inhibits the phagocytosis and the reactive oxygen species (ROS) generation of peritoneal macrophages (M?s), and that insulin-like growth factor-1(IGF-1) and mechano-growth factor (MGF) produced by macrophages may contribute to this process. Rats were randomized to two groups, sedentary control group (n = 10) and overload training group (n = 10). The rats of overload training group were subjected to 11 weeks of experimental training protocol. Blood sample was used to determine the content of hemoglobin, testosterone, and corticosterone. The phagocytosis and the ROS generation of M?s were measured by the uptake of neutral red and the flow cytometry, respectively. IGF-1 and MGF mRNA levels in M?s were determined by real-time PCR. In addition, we evaluated the effects of IGF-1 and MGF peptide on phagocytosis and ROS generation of M?s in vitro. The data showed that overload training significantly decreased the body weight (19.3 %, P < 0.01), the hemoglobin (13.5 %, P < 0.01), the testosterone (55.3 %, P < 0.01) and the corticosterone (40.6 %, P < 0.01) in blood. Moreover, overload training significantly decreased the phagocytosis (27 %, P < 0.05) and the ROS generation (35 %, P < 0.01) of M?s. IGF-1 and MGF mRNA levels in M?s from overload training group increased significantly compared with the control group (21-fold and 92-fold, respectively; P < 0.01). In vitro experiments showed that IGF-1 had no significant effect on the phagocytosis and the ROS generation of M?s. Unlike IGF-1, MGF peptide impaired the phagocytosis of M?s in dose-independent manner. In addition, MGF peptide of some concentrations (i.e., 1, 10, 50, 100 ng/ml) significantly inhibited the ROS generation of M?s. These results suggest that overload training inhibits the phagocytosis and the ROS generation of peritoneal macrophages, and that MGF produced by macrophages may play a key role in this process. This may represent a novel mechanism of immune suppression induced by overload training.     

Ventilatory muscle strength, diaphragm thickness and pulmonary function in world-class powerlifters

Purpose

Resistance training activates the ventilatory muscles providing a stimulus similar to ventilatory muscle training. We examined the effects of elite powerlifting training upon ventilatory muscle strength, pulmonary function and diaphragm thickness in world-class powerlifters (POWER) and a control group (CON) with no history of endurance or resistance training, matched for age, height and body mass.

Methods

Body composition was assessed using single-frequency bioelectrical impedance. Maximal static volitional inspiratory (P _I,max) and expiratory (P _E,max) mouth pressures, diaphragm thickness (T _di) derived from ultrasound measurements and pulmonary function from maximal flow volume loops were measured.

Results

There were no differences in physical characteristics or pulmonary function between groups. P _I,max (22 %, P < 0.05, effect size d = 1.13), P _E,max (16 %, P = 0.07, effect size d = 0.86) and T _di (27 %, P < 0.01, effect size d = 1.59) were greater in POWER than CON. Correlations were observed between both T _di and P _I,max (r = 0.518, P < 0.05), T _di and P _E,max (r = 0.671, P < 0.01) and T _di and body mass (r = 0.502, P < 0.05).

Conclusions

We conclude that manoeuvres performed by world-class powerlifters improve ventilatory muscle strength and increases diaphragm size. Whole-body resistance training may be an appropriate training mode to attenuate the effects of ventilatory muscle weakness experienced with ageing and some disease states.     

Osteogenic Responses to Different Concentrations/Ratios of BMP-2 and bFGF in Bone Formation

Recombinant human bone morphogenetic protein-2 (rhBMP-2) and basic fibroblast growth factor (bFGF) are the focus of research pertaining to the stimulation of bone formation. We ascertained the effects of different concentrations rhBMP-2 on proliferation and differentiation of bone marrow stromal cells (BMSCs) in vitro and on ectopic bone formation in rats. BMSCs were obtained from beagle dogs and cultured in medium containing different concentrations rhBMP-2 and bFGF (0, 25, 50, 100, or 200 ng/mL). In a separate experiment, BMSCs were treated with different ratios (1:1, 2:1, 4:1, or 8:1) of rhBMP to bFGF (in each case the concentration of rhBMP was 100 ng/mL and the bFGF concentrations 100, 50, 25, or 12.5 ng/mL). Proliferation and differentiation of BMSCs were quantified by assessing methyl thiazole tetrazolium (MTT) and alkaline phosphatase (ALP) over 6 consecutive days. Von Kossa staining was performed on day 6. For the in vivo tests, porous calcium phosphate cement (CPC) was seeded with BMSCs (5 × 10⁴) in medium containing 100 ng/mL rhBMP-2, 50 ng/mL bFGF or combined 100 ng/mL rhBMP-2 and 50 ng/mL bFGF. These cells were then subcutaneously implanted in four sites in nude rats. Bone formation was detected by histology at weeks 4 and 12 and quantified using a KS400 computer based image analysis system. It was determined that combined rhBMP-2 and bFGF at a ratio of 2:1 (100:50 ng/mL) promoted significantly increased BMSC proliferation and differentiation of BMSCs compared to rhBMP-2 or bFGF alone (p < 0.05). CPC with combined 100 ng/mL rhBMP-2 and 50 ng/mL bFGF stimulated more bone formation than either 100 ng/mL rhBMP-2 or 100 ng/mL bFGF (p < 0.05). These results show that a combination of rhBMP-2 and bFGF effectively induces early BMSC proliferation and differentiation in vitro. When combined, rhBMP-2 and bFGF synergistically promote new bone formation.     

Determination of effective dose combination of Azadirachta indica leaf extracts and diminazene diaceturate in the treatment of experimental Trypanosoma brucei brucei infection in rats

This study investigated the effective dose of methanolic Azadirachta indica leaf extracts, MAILE, combined with diminazene diaceturate, DDA, in the treatment of experimental Trypanosoma brucei brucei infection in rats. Acute toxicity study of the drug and extract combinations was carried in non-infected rats. Eleven different groups of ten rats each were used. Ten out of the eleven groups were infected with T. brucei brucei and used to determine the effective dose of MAILE and DDA combination to be used in the treatment of the infection. All the infected rats were treated, viz, 7.0 mg/kg body weight (bw) DDA plus 500 mg/kg bw MAILE (group 1); 7.0 mg/kg body bw DDA plus 250 mg/kg bw MAILE (group 2); 7.0 mg/kg body bw DDA plus 125 mg/kg bw MAILE (group 3); 3.5 mg/kg body bw DDA plus 500 mg/kg bw MAILE (group 4); 3.5 mg/kg body bw DDA plus 250 mg/kg bw MAILE (group 5); 3.5 mg/kg body bw DDA plus 125 mg/kg bw MAILE (group 6); 1.8 mg/kg bw DDA plus 500 mg/kg bw MAILE (group 7); 1.8 mg/kg bw DDA plus 250 mg/kg bw MAILE (group 8); 1.8 mg/kg body bw DDA plus 125 mg/kg bw MAILE (group 9). Two other groups, infected untreated (group 10) and uninfected untreated (group 11), served as negative and positive control, respectively. The parameters assessed to determine the effective dose combination of the two were onset of parasitaemia (OP), level of parasitaemia (LOP), clearance of parasites post-treatment (COPPT), relapse of infection period (RIP), erythrocyte counts (EC), packed cell volume (PCV) and total leucocyte counts (TLC). There was no significant difference (p?<?0.05) in OP between the groups. A day following treatment, the LOP of groups 1, 2, 3 and 4 was found to be significantly lower (p?<?0.05) than that of groups 5 and 6 (p?<?0.05) which in turn was lower (p?<?0.05) than that of groups 7, 8 and 9, respectively. The mean COPPT of groups 5 and 6 was significantly (p?<?0.05) longer than that of groups 1, 2, 3 and 4. There was no significant difference (p?<?0.05) in the mean COPPT among groups 1, 2, 3 and 4. There was no clearance of parasites in groups 7, 8 and 9. The mean RIP of group 5 and 6 was significantly shorter (p?<?0.05) than in group 4. There was no relapse of infection in group 1, 2 and 3 rats. Rats in groups 1, 2, 3 and 4 had significantly higher (p?<?0.05) PCV, EC and TLC 10 days post-treatment, and that trend continued throughout the experimental period when compared to other infected groups. It was concluded that dose combination of 125 mg/kg bw extract plus 7 mg/kg bw DDA was the best dose combination judging from the parameters assessed.     

Elastic properties of peripheral arteries in heart failure patients in comparison with normal subjects

Understanding the change in elastic properties of peripheral arteries in heart failure patients is of particular importance, especially when compared with normal subjects. To investigate factors associated with their difference, 40 normal subjects and 60 heart failure patients were studied. Electrocardiograms, carotid pulses and radial pulses were simultaneously recorded to determine carotid-radial pulse transit time (carotid-radial PTT), arm pulse wave velocity (PWV), and arterial volume distensibility. In comparison with normal subjects, carotid-radial PTT was lower by 8 ms in heart failure patients, arm PWV higher by 1.4 m/s, and peripheral arterial distensibility lower by 0.04 % per mmHg (all significant, P < 0.01). Peripheral arterial distensibility was significantly related to systolic blood pressure (SBP) and to left ventricular ejection fraction (LVEF) for heart failure patients (both P < 0.001), but the relationship for the normal group was not statistically significant (both 0.05 < P<0.1). Ageing had a significant inverse relationship with arterial distensibility in normal subjects (P < 0.05), but not in heart failure patients (P = 0.59). No subject in the normal group had an arterial distensibility lower than 0.1 % per mmHg, in comparison with 28 % (17/60) in the heart failure group. Peripheral arterial distensibility has been shown to be significantly lower in heart failure patients in comparison with normal subjects. High SBP and low LVEF were the main factors associated with low arterial distensibility in heart failure patients.     

The Effect of SHJKS on Cytokines Production and NF-κB Activation in the Peripheral Blood Mononuclear Cells of Patients with Cerebral Infarction

The Korean genuine medicine “Seonghyangjeongkisan” (SHJKS) has long been used for various cerebrovascular diseases. However, very little scientific investigation has been carried out. Cytokines involved in the regulation of inflammatory reactions and immune responses may play a role in the pathogenesis of cerebral infarction (CI). The aim of the present study is to elucidate how SHJKS modulates the inflammatory reaction in lipopolysaccaride (LPS) plus phytohaemagglutinin (PHA)-stimulated peripheral mononuclear cells (PBMCs) from CI patients. The amount of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in PBMC culture supernatant was significantly increased in the LPS plus PHA treated cells compared to unstimulated cells. SHJKS inhibited the TNF-α, IL-1β, IL-6, and IL-8 production in dose dependent manner. Maximal inhibition rate of the TNF-α, IL-1β, IL-6, and IL-8 by SHJGS (1.0 mg/ml) was 68.01 ± 0.28% (P < 0.01), 52.11 ± 0.56 % (P < 0.01), 53.42 ± 0.46 % (P < 0.01), and 46.70 ± 0.37% (P < 0.05), respectively. In addition, we show that SHJKS suppressed nuclear factor (NF)-κB activation induced by LPS plus PHA, leading to suppression of IκB-α phosphorylation and degradation. These results suggest that SHJKS might have regulatory effects on LPS plus PHA-induced cytokine production and NF-κB activation, which might explain its beneficial effect in the treatment of CI.     

Palosuran Treatment Effective as Bosentan in the Treatment Model of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder that any valuable advance in the management of diseases has crucial importance. The present study aimed to compare the Endothelin1 (ET1) inhibitor bosentan which is regarded as standard therapy with different dose regimens of palosuran which is urotensin-II (UII) inhibitor and explore the discrepancy for mean pulmonary arterial pressure (mPAP), UII, ET1 levels, and pulmonary vascular pathology. Seventy rats were randomly divided into seven groups of ten animals each: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran 30 mg) received subcutaneous MCT and palosuran. Other groups consist of group 4 (MCT + palosuran 100 mg), group 5 (MCT + bosentan 30 mg), group 6 (MCT + bosentan 100 mg), and group 7 (combination therapy). Serum ET1, UII, mPAP levels, and pulmonary arteriolar pathology of different diameter vessels of all groups have been measured and recorded. The ET1 and UII levels of untreated rats (group 2) were significantly higher than the other groups (p?<?0.05). Moreover, mPAP levels of group 2 were significantly higher than the other groups (p?=?0.001). Finally, 50–125-μm diameter of arteriole wall thickness was found to be significantly thicker in monocrotaline group compared to groups 4 and 6 (p?<?0.001). Statistical differences of wall thickness/diameter ratios of arteries and arterioles larger than 125 was found to be significant between group 5, group 6, and the control group (p?<?0.001). UII inhibitor is at least as effective as standard therapy bosentan. Findings of this study consolidate that palosuran could be a new future promising therapeutic option in PAH.     

Protective effects of ascorbic acid and garlic extract against neurogenesis inhibition caused by developmental lead exposure in the dentate gyrus of rat

Lead is a well-known neurotoxin that affects the developing central nervous system and may potentially inhibit neurogenesis in adults. We investigated the effect of ascorbic acid and garlic extract against lead-induced neurotoxicity in developing rat dentate gyrus. Female Wistar rats were divided randomly into five groups: lead-treated (L; 1,500 ppm lead acetate in drinking water) group, lead plus ascorbic acid-treated (L?+?AA; 500 mg/kg, ip) group, lead plus garlic juice-treated (L?+?G; 1 ml /100 g BW, gavage) group, sham group (sh), and controls. All treatments were administered to female rats during pregnancy and lactation. At the end of the treatment, dentate gyrus neurogenesis were determined using Doublecortin (DCX) immunohistochemistry in the hippocampus of 50-day-old male pups. DCX-positive cells in the dentate gyrus were counted and compared between the groups. Lead exposure caused a significant increase in blood and brain lead concentration vs. control (P?<?0.001); whereas, co-administration of ascorbic acid or garlic?+?lead was effective in reducing blood and brain lead levels (P?<?0.01). The number of DCX-positive cells in the dentate gyrus of the lead-exposed group was significantly lower, when compared with controls. A statistically significant increase in number of DCX-positive cells in ascorbic acid and garlic groups compared with lead-exposed rats was noted (P?<?0.05). This study provides evidence of the beneficial role of ascorbic acid and garlic in early status of dentate gyrus neurogenesis in rats against lead exposure.     

Urinary trypsin inhibitor suppresses excessive generation of superoxide anion radical, systemic inflammation, oxidative stress, and endothelial injury in endotoxemic rats

Objective and design

The protective effects of ulinastatin, a human urinary trypsin inhibitor (UTI), against superoxide radical (O ₂ ^?· ) generation, systemic inflammation, lipid peroxidation, and endothelial injury were investigated in endotoxemic rats.

Materials and treatment

Twenty-one Wistar rats were allocated to a control group, a UTI group, and a sham group. A bolus of lipopolysaccharide (LPS; 3 μg/g) was administered intravenously to the control group, a bolus of LPS and UTI (5 U/g) to the UTI group, and a bolus of saline to the sham group.

Methods

The O ₂ ^?· generated was measured as the current in the right atrium using an electrochemical O ₂ ^?· sensor. Plasma nitrite, high mobility group box 1 (HMGB1), tumor necrosis factor (TNF)-α, inteleukin (IL)-6, malondialdehyde, and soluble intercellular adhesion molecule-1 (sICAM-1) were measured 360 min after LPS administration.

Results

The O ₂ ^?· current increased in the control group and was significantly attenuated in the UTI group after 55 min (P < 0.05 at 55–60 min, P < 0.01 at 65–360 min). Plasma nitrite, HMGB1, TNF-α, IL-6, malondialdehyde, and sICAM-1 were attenuated in the UTI group.

Conclusions

UTI suppressed excessive O ₂ ^?· generation, systemic inflammation, lipid peroxidation, and endothelial injury in endotoxemic rats.     

The effects of soy and tamoxifen on apoptosis in the hippocampus and dentate gyrus in a pentylenetetrazole-induced seizure model of ovariectomized rats

The effects of tamoxifen and soy on apoptosis of the hippocampus and dentate gyrus of ovariectomized rats after repeated seizures were investigated. Female rats were divided into: (1) Control, (2) Sham, (3) Sham-Tamoxifen (Sham-T), (4) Ovariectomized (OVX), (5) OVX-Tamoxifen (OVX-T), (6)OVX-Soy(OVX-S) and (7) OVX-S-T. The animals in the OVX-S, OVX-T and OVX-S-T groups received soy extract (60 mg/kg; i.p.), tamoxifen (10 mg/kg) or both for 2 weeks before induction of seizures. The animals in these groups additionally received the mentioned treatments before each injection of pentylenetetrazole (PTZ; 40 mg/kg) for 6 days. The animals in the Sham and OVX groups received a vehicle of tamoxifen and soy. A significant decrease in the seizure score and TUNEL-positive neurons was seen in the OVX group compared to the Sham (P < 0.001). The animals in both the OVX-T and OVX-S groups had a significantly higher seizure score as well as number of TUNEL-positive neurons compared to the OVX group (P < 0.01–P < 0.001). Co-treatment of the OVX rats by the extract and tamoxifen decreased the seizure score and number of TUNEL-positive neurons compared to OVX-S (P < 0.001). Treatment of the OVX rats by either soy or tamoxifen increased the seizure score as well as the number of TUNEL-positive neurons in the hippocampal formation. Co-administration of tamoxifen and soy extract inhibited the effects of the soy extract and tamoxifen when they were administered alone. It might be suggested that both soy and tamoxifen have agonistic effects on estrogen receptors by changing the seizure severity.     

Dimethyl Sulfoxide Attenuates Acute Lung Injury Induced by Hemorrhagic Shock/Resuscitation in Rats

Inflammation following hemorrhagic shock/resuscitation (HS/RES) induces acute lung injury (ALI). Dimethyl sulfoxide (DMSO) possesses anti-inflammatory and antioxidative capacities. We sought to clarify whether DMSO could attenuate ALI induced by HS/RES. Male Sprague-Dawley rats were allocated to receive either a sham operation, sham plus DMSO, HS/RES, or HS/RES plus DMSO, and these were denoted as the Sham, Sham?+?DMSO, HS/RES, or HS/RES?+?DMSO group, respectively (n?=?12 in each group). HS/RES was achieved by drawing blood to lower mean arterial pressure (40–45 mmHg for 60 min) followed by reinfusion with shed blood/saline mixtures. All rats received an intravenous injection of normal saline or DMSO immediately before resuscitation or at matching points relative to the sham groups. Arterial blood gas and histological assays (including histopathology, neutrophil infiltration, and lung water content) confirmed that HS/RES induced ALI. Significant increases in pulmonary expression of tumor necrosis factor-α (TNF-α), malondialdehyde, nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) confirmed that HS/RES induced pulmonary inflammation and oxidative stress. DMSO significantly attenuated the pulmonary inflammation and ALI induced by HS/RES. The mechanisms for this may involve reducing inflammation and oxidative stress through inhibition of pulmonary NF-κB, TNF-α, iNOS, and COX-2 expression.