The effect of epidermal growth factor on the incremental Young's moduli in the rat small intestine

Biomechanical remodelling of the rat small intestine after treatment with epidermal growth factor (EGF) subcutaneously for 2 days (n=6), 4 days (n=6), 7 days (n=6), and 14 days (n=4) was studied. The incremental circumferential, longitudinal and cross moduli close to the in vivo state were computed from bi-axial test data (combined inflation and axial stretching) by a least square method. The moduli in the circumferential direction and the longitudinal direction differed in all groups, i.e. the mechanical properties were anisotropic in both normal and EGF-treated rats. Time-dependent variation existed for the Young's moduli in all directions during EGF treatment (P<0.05). The circumferential modulus decreased during the first 7 days of EGF treatment and it almost remodelled back to that of the control group after 14 days treatment. The incremental modulus in the circumferential direction ranged between 17.4 and 24.2 kPa. The modulus in the longitudinal direction ranged between 22.9 and 32.4 kPa. The longitudinal modulus after 4 days EGF treatment was significantly larger than that of control group (P<0.02). The cross modulus decreased during the first 4 days of EGF treatment thereafter it increased to a maximum at 7 days. The values for the cross moduli were between 4.7 and 6.6 kPa. In conclusion, the mechanical properties in the intestinal wall are anisotropic and remodel during treatment with EGF.     

Effect of re-feeding after starvation on biomechanical properties in rat small intestine.

Luminal nutrients are essential for maintaining the structural and functional integrity of the gut. Starvation induces pronounced structural and biomechanical remodelling in the rat small intestine. The present work was done to study the recovery process after resumption of food intake. Twenty-five Wistar rats were allocated to five groups. Four groups fasted for 7 days but had free access to water. One of these groups served as fasted controls and was killed at the end of the fast. The other three groups were re-fed for 2, 4 and 7 days before they were euthanised. The fifth group had free access to food during the whole study (fed controls). The intestinal no-load state, zero-stress state and the stress-strain relationship during distension were studied. The intestinal segments were cut transversely into a series of short ring-shaped segments to obtain the no-load state. Each ring was cut in the radial direction to obtain the zero-stress state. The rats regained the lost body weight (22%) by the 7th day of re-feeding. The lost duodenal mass (40%) and jejunal mass (25%) were regained by the 2nd day whereas the lost mass from ileum (18%) was regained by the 4th day. The fasting-induced morphometric changes were normalised by re-feeding on the 2nd day in the duodenum and jejunum, and on the 4th day in the ileum. The longitudinal stress-strain curves shifted to the right after fasting and shifted back within two days following re-feeding (P<0.05). The circumferential stress-strain curves in the fasted or re-fed rats changed in a similar though less pronounced way. Normal values were reached within 4-7 days for the circumferential direction. In conclusion, fasting-induced biomechanical and structural remodelling were normalised by re-feeding in a time- and location-dependent way.     

Effect of Recombinant Human Epidermal Growth Factor Against Cutaneous Scar Formation in Murine Full-thickness Wound Healing

A visible cutaneous scar develops from the excess formation of immature collagen in response to an inflammatory reaction. This study examined the role of epidermal growth factor (EGF) in the formation of cutaneous scars. Twenty Crl:CD-1 (ICR) mice were used and 2 full-thickness skin wounds were made on the dorsum of each mouse. One of the wounds was treated with recombinant human EGF by local application and the other was treated with saline for control until complete healing was achieved. The EGF-treated group''s wounds healed faster than the control group''s. The width of the scar was smaller by 30% and the area was smaller by 26% in the EGF-treated group. Inflammatory cell numbers were significantly lower in the EGF-treated group. The expression of transforming growth factor (TGF)-β₁ in the EGF-treated group was increased. It was observed that the amount of collagen in the EGF-treated group was larger than the control group. In the EGF-treated group, the visible external scars were less noticeable than that in the control group. These results suggest that EGF can reduce cutaneous scars by suppressing inflammatory reactions, decreasing expression of TGF-β₁, and mediating the formation of collagen.     

Ultrastructural changes in blood vessels in epidermal growth factor treated experimental cutaneous wound model

This study investigates the impact of epidermal growth factor (EGF) on blood vessels, specifically on the development of intussusceptive angiogenesis in cutaneous wound healing. Excisional wounds were formed on both sides of the medulla spinalis in dorsal location of the rats. The control and EGF-treated groups were divided into two groups with respect to sacrifice day: 5 d and 7 d. EGF was topically applied to the EGF-treated group once a day. The wound tissue was removed from rats, embedded in araldite and paraffin, and then examined under transmission electron and light microscopes. The ultrastructural signs of intussusceptive angiogenesis, such as intraluminal protrusion of endothelial cells and formation of the contact zone of opposite endothelial cells, were observed in the wound. Our statistical analyses, based on light microscopy observations, also confirm that EGF treatment induces intussusceptive angiogenesis. Moreover, we found that induction of EGF impact on intussusceptive angiogenesis is higher on the 7th day of treatment than on the 5th day. This implies that the duration of EGF treatment is important. This research clarifies the effects of EGF on the vessels and proves that EGF induces intussusceptive angiogenesis, being a newer model with respect to sprouting type.     

Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett’s esophagus

In esophageal neoplasms, the histopathologic differentiation between Barrett’s esophagus with or without intraepithelial neoplasia and adenocarcinoma is often challenging. Immunohistochemistry might help to differentiate between these lesions. The expression of CDX2, LI-cadherin, mucin 2 (MUC2), blood group 8 (BG8, Lewis^y), claudin-2, and villin was investigated in normal gastroesophageal (n = 23) and in Barrett’s (n = 17) mucosa, in low-grade (n = 12) and high-grade (n = 9) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. For CDX2 and LI-cadherin, the immunoreactivity score was highest in IEN while for MUC2, BG8, and villin, it dropped gradually from Barrett’s via IEN to adenocarcinoma, and expression of Claudin-2 was only weak and focal in all lesions. The expression of MUC2 and LI-cadherin differed significantly between all examined lesions except between low-grade and high-grade IEN. MUC2 and LI-cadherin are useful immunohistochemical markers for the differentiation between normal glandular mucosa, Barrett’s mucosa, IEN, and invasive carcinoma of the esophagus; however, none of the examined markers was helpful for the differentiation between low-grade and high-grade IEN.     

Induction of striatal neurogenesis enhances functional recovery in an adult animal model of neonatal hypoxic-ischemic brain injury

While intraventricular administration of epidermal growth factor (EGF) expands the proliferation of neural stem/progenitor cells in the subventricular zone (SVZ), overexpression of brain-derived neurotrophic factor (BDNF) is particularly effective in enhancing striatal neurogenesis. We assessed the induction of striatal neurogenesis and consequent functional recovery after chronic infusion of BDNF and EGF in an adult animal model of neonatal hypoxic-ischemic (HI) brain injury. Permanent brain damage was induced in CD-1® (ICR) mice (P7) by applying the ligation of unilateral carotid artery and hypoxic condition. At 6 weeks of age, the mice were randomly assigned to groups receiving a continuous 2-week infusion of one of the following treatments into the ventricle: BDNF, EGF, BDNF/EGF, or phosphate buffered saline (PBS). Two weeks after treatment, immunohistochemical analysis revealed an increase in the number of BrdU⁺ cells in the SVZ and striata of BDNF/EGF-treated mice. The number of new neurons co-stained with BrdU and βIII-tubulin was also significantly increased in the neostriata of BDNF/EGF-treated mice, compared with PBS group. In addition, the newly generated cells were expressed as migrating neuroblasts labeled with PSA-NCAM or doublecortin in the SVZ and the ventricular side of neostriata. The new striatal neurons were also differentiated as mature neurons co-labeled with BrdU⁺/NeuN⁺. When evaluated post-surgical 8 weeks, BDNF/EGF-treated mice exhibited significantly longer rotarod latencies at constant speed (48 rpm) and under accelerating condition (4–80 rpm), relative to PBS and untreated controls. In the forelimb-use asymmetry test, BDNF/EGF-treated mice showed significant improvement in the use of the contralateral forelimb. In contrast, this BDNF/EGF-associated functional recovery was abolished in mice receiving a co-infusion of 2% cytosine-b-d-arabinofuranoside (Ara-C), a mitotic inhibitor. Induction of striatal neurogenesis by the intraventricular administration of BDNF and EGF promoted functional recovery in an adult animal model of neonatal HI brain injury. The effect of Ara-C to completely block functional recovery indicates that the effect may be the result of newly generated neurons. Therefore, this treatment may offer a promising strategy for the restoration of motor function for adults with cerebral palsy (CP).     

正常大鼠不同动脉血管应力-应变分布的比较

通过充压实验和无载荷状态及零应力状态,我们研究了16只雄性大鼠的胸主动脉、腹主动脉、左颈总动脉、左股动脉和左肺动脉的形态学和应力－应变分布特征,并比较了不同血管间的差异。结果表明,血管的内外周长、管壁和管腔面积、管壁厚度、管壁厚度与内半径之比以及在不同压力负荷下血管外直径的变化,五条动脉之间有显著差异（P＜0.01）。展开角在肺动脉最大,而胸主动脉最小（P＜0.01）。残余应变绝对值和残余应变梯度在股动脉最大,而在胸主动脉最小（P＜0.01）。应力－应变关系分析证明,在周向上,股动脉最硬;在轴向上,胸主动脉最硬。而在这两个方向上,肺动脉最软。本实验表明,无论在形态学指数方面,还是在生物力学特征方面,五条动脉血管间都有显著差异。     

The prognosis after multidisciplinary treatment for patients with postinfectious chronic fatigue syndrome and noninfectious chronic fatigue syndrome

The prognosis after multidisciplinary treatment for patients with postinfectious chronic fatigue syndrome (CFS, n = 9) and noninfectious CFS (n = 9) was clarified. After treatment, natural killer (NK) cell activity increased in the postinfectious CFS group but did not recover to within normal range in the noninfectious CFS group. In the postinfectious CFS group, physical and mental symptoms improved, and 8 patients returned to work. In the noninfectious CFS group, symptoms did not improve, and only 3 patients returned to work. The prognosis of postinfectious CFS group was better than that of noninfectious CFS group. Classification of CFS patients into postinfectious and noninfectious groups is useful for choosing the appropriate treatment in order to obtain better prognosis.     

Epidermal Growth Factor Promotes Proliferation and Improves Restoration After Intestinal Ischemia–Reperfusion Injury in Rats

Epidermal growth factor (EGF) is an attractive and promising therapeutic application for intestinal disorders. The current study examined its influence on proliferation and restoration after ischemia–reperfusion (I/R) injury in rat small intestine. Six groups were performed: sham operation (Con); ischemia for 30 min with subsequent reperfusion for 30 min (I/R); I/R injured with 500 μg/kg EGF injected 5 min before ischemia (Pre-l); I/R injured with 50 μg/kg EGF injected 5 min before ischemia (Pre-s); I/R injured with 500 μg/kg EGF injected 5 min after reperfusion (Post-l); and I/R injured with 50 μg/kg EGF injected 5 min after reperfusion (Post-s). Intestinal histological damage, crypt cell proliferation degree, mucosal permeability, tight junction proteins expression, and levels of inflammation factors were studied for each group. Compared with the I/R group, administration of EGF in the Pre-l, Pre-s, and Post-l groups all presented a significant proliferation effect. The levels of FD4, IL-6, and TNF-α were dramatically decreased in all EGF-treated groups. Histological destruction was improved and TJs recovery was notably accelerated in all EGF-treated groups except the Post-s group. d-lactate concentration was only diminished in the Pre-l group. These results suggest that mucosally applied EGF can promote intestinal proliferation and improve restoration after I/R injury. EGF intraluminal administration is an effective treatment against intestinal I/R injury.     

Influence of Innate Immune Responses on Autoimmunity

Objective: To explore the therapeutic alliance effects of adenovirus vector-mediated gene transfer of ICOSIg and CTLA4Ig fusion protein on experimental autoimmune myocarditis (EAM).

Methods: Expression vector pAdeno-CTLA4Ig and pAdeno-ICOSIg was constructed and transfected into HEK293 cells. Adenovirus expresses CTLA4Ig and ICOSIg was produced. Ad-CMV-GFP was used as controls. EAM was induced in Lewis rats by injection of procine cardiac myosin. All the immunized rats were divided into four groups. Group A (n = 15) received adenovirus containing CTLA4Ig and ICOSIg from day 14–28; group B (n = 15), group C (n = 15) and group D (n = 15) received adenovirus containing CTLA4Ig, ICOSIg and GFP, respectively. Group E (n = 10) was normal controls never received immunization. On day 28, all the rats were killed after echocardiography examination. Histopathological examination was used to observe inflammation in the myocardium. Western blot was used to detect CTLA4, ICOS, ICOSL and competitive RT-PCR for B7-1, B7-2 expression. T lymphocyte proliferation assay was performed and ELISPOT was used to detect the Th1 and Th2 production.

Results: Alliance application of CTLA4Ig and ICOSIg exerts therapeutic effects on EAM. After a treatment duration of 14 days, cardiac function and myocardial inflammation improved significantly compared to group D. Expression of CTLA-4, ICOS and ICOSL, B7-1 was statistically decreased in group A, B and C compared with group D. T-cell proliferation was inhibited by costimulatory blockade in a dose-dependent style. ICOSIg blockade significantly augments IL-4 and IL-10 production while diminished IFN-γ production.

Conclusions: Blockade of costimulatory pathway with alliance therapy of CTLA4Ig and ICOSIg alleviated autoimmune damage in EAM and improved cardiac function. The mechanisms may be downregulation of costimulatory molecules and anti-inflammation.     

Epidermal growth factor and insulin short‐term increase hPepT1‐mediated glycylsarcosine uptake in Caco‐2 cells

Aims: Little is known about the physiological regulation of the human intestinal di/tri‐peptide transporter, hPepT1. In the present study we evaluated the effects of epidermal growth factor (EGF) and insulin on hPepT1‐mediated dipeptide uptake in the intestinal cell line Caco‐2. Methods: Caco‐2 cells were grown on filters for 23–27 days. Apical dipeptide uptake was measured using [¹⁴C]glycylsarcosine([¹⁴C]Gly‐Sar). HPepT1 mRNA levels were investigated using RT‐PCR, cytosolic pH was determined using the pH‐sensitive fluorescent probe BCECF. Results: Basolateral application of EGF increased [¹⁴C]Gly‐Sar uptake with an ED₅₀ value of 0.77 ± 0.25 ng mL^?1 (n = 3?6) and a maximal stimulation of 33 ± 2% (n = 3?6). Insulin stimulated [¹⁴C]Gly‐Sar uptake with an ED₅₀ value of 3.5 ± 2.0 ng mL^?1 (n = 3?6) and a maximal stimulation of approximately 18% (n = 3?6). Gly‐Sar uptake followed simple Michaelis‐Menten kinetics. K_m in control cells was 0.98 ± 0.11 mM (n = 8) and V_max was 1.86 ± 0.07 nmol cm^?2 min^?1 (n = 8). In monolayers treated with 200 ng mL^?1 of EGF, K_m was 1.11 ± 0.05 mM (n = 5) and V_max was 2.79 ± 0.05 nmol cm^?2 min^?1 (n = 5). In monolayers treated with 50 ng mL^?1 insulin, K_m was 1.03 ± 0.08 mM and V_max was 2.19 ± 0.06 nmol cm^?2 min^?1 (n = 5). Kinetic data thus indicates an increase in the number of active transporters, following stimulation. The incrased Gly‐Sar uptake was not accompanied by changes in hPepT1 mRNA, nor by measurable changes in cytosolic pH. Conclusions: Short‐term stimulation with EGF and insulin caused an increase in hPepT1‐mediated uptake of Gly‐Sar in Caco‐2 cell monolayers, which could not be accounted for by changes in hPepT1 mRNA or proton‐motive driving force.     

The effect of streptozotocin-induced diabetes mellitus on urinary excretion of sodium and renal Na+−K+-ATPase activity

Renal sodium handling and microsomal Na⁺–K⁺-ATPase activity in kidney cortex, medulla and papilla of rats with streptozotocin-induced diabetes mellitus (DM) was studied.During 7 days following the administration of streptozotocin GFR, urinary excretion, filtered load and tubular reabsorption of Na⁺ averaged (mean±SE) 1.18±0.016 ml/min, 1.74±0.14, 177.3±8.9 and 175.6±8.9 mEq/min respectively in experimental rats as compared to corresponding rates of 0.85±0.04 (P<0.001), 0.85±0.03 (P<0.001), 129.8±5.8 (P<0.001) and 129±5.8 (P<0.001) respectively in the control rats.The activity of microsomal Na–K-ATPase in the kidney cortex, medulla and papilla of the control group was (mean±SE) 44.7±1.7, 150±7.5 and 37.4±3.6 (moles Pi/mg prot/h) respectively. 24 h after DM induction Na–K-ATPase activity in the cortex rose to 59.3±2.4 (P<0.001) and remained high after 3 and 7 days. Medullary Na–K-ATPase activity was unchanged 24 h after streptozotocin administration but was markedly increased to 260±9 (P<0.001) after 3 days and remained high after 7 days.These findings show that stretozotocin-induced DM in rats causes a substantial increase in GFR which is associated with a net increase in filtered and reabsorbed load of Na⁺ and natriuresis. These alterations are accompanied by a marked increase in Na–K-ATPase activity in renal medulla and in the cortex.This study was supported by the Morton S. Kaufman Hemodialysis Foundation and by the Joint Research Fund of the Hebrew University and Hadassah     

Parallel changes in red blood cell and renal Na−K-ATPase activity in adrenal and electrolyte disorders in the rat

To compare the activity of Na–K-ATPase in the red blood cells (RBCs) and in renal tissue in disorders of Na⁺ metabolism, the following groups of rats were studied: 1) control, intact rats, 2) adrenalectomized (ADX) rats, 3) intact rats treated with DOCA, 4) ADX DOCA-treated rats, 5) intact salt-loaded rats, 6) ADX salt-loaded rats, 7) intact dexamethasone-treated rats (DEXA), and 8) ADX DEXA-treated rats. After adrenalectomy (group 2) serum Na¹ decreased and serum K⁺ increased.Renal Na–K-ATPase in cortex, medulla and papilla of the control group was 44±2.7 mol Pi/mg prot/h, 128.2±5.9 and 44±3.2 respectively and in group 2 the enzyme activity was 32.5±2.0 (P<0.005), 81.7±4.5 (P<0.001) and 23.6±1.9 (P<0.001) respectively. RBCs Na–K-ATPase of control animals was 2.82±0.19 mol Pi/mg prot/h, while in group 2 the activity was 1.43±0.24 (P<0.001). DOCA treatment of ADX rats (group 4) normalized serum electrolytes and Na–K-ATPase activity in the renal cortex and papilla and in the RBCs. In the renal medulla the correction by DOCA was only partial. Salt loading of ADX rats (group 6) normalized serum electrolytes and Na–K-ATPase activity in the renal medulla and RBCs. Salt loading of normal rats increased RBC Na–K-ATPase to 3.72±0.36 (P<0.02) and medullary Na–K-ATPase to 185.6±9.8 (P<0.01). DEXA treatment of ADX rats (group 8) corrected only partially the abnormalities in serum electrolytes and Na–K-ATPase activity in the kidney and in the RBCs. These findings show, 1) parallel changes in the activity of Na–K-ATPase in the RBCs and in the kidney after adrenalectomy, 2) parallel changes in the enzyme activity in RBCs and in the kidney medulla after salt loading, and 3) correction towards normal of RBC Na–K-ATPase after ADX by NaCl and DOCA treatment.This study was supported by the Morton S. Kaufman Hemodialysis Foundation     

Increased blood–brain barrier permeability in mammalian brain 7 days after exposure to the radiation from a GSM-900 mobile phone

Microwaves were for the first time produced by humans in 1886 when radio waves were broadcasted and received. Until then microwaves had only existed as a part of the cosmic background radiation since the birth of universe. By the following utilization of microwaves in telegraph communication, radars, television and above all, in the modern mobile phone technology, mankind is today exposed to microwaves at a level up to 10²⁰ times the original background radiation since the birth of universe.Our group has earlier shown that the electromagnetic radiation emitted by mobile phones alters the permeability of the blood–brain barrier (BBB), resulting in albumin extravasation immediately and 14 days after 2 h of exposure.In the background section of this report, we present a thorough review of the literature on the demonstrated effects (or lack of effects) of microwave exposure upon the BBB.Furthermore, we have continued our own studies by investigating the effects of GSM mobile phone radiation upon the blood–brain barrier permeability of rats 7 days after one occasion of 2 h of exposure. Forty-eight rats were exposed in TEM-cells for 2 h at non-thermal specific absorption rates (SARs) of 0 mW/kg, 0.12 mW/kg, 1.2 mW/kg, 12 mW/kg and 120 mW/kg. Albumin extravasation over the BBB, neuronal albumin uptake and neuronal damage were assessed.Albumin extravasation was enhanced in the mobile phone exposed rats as compared to sham controls after this 7-day recovery period (Fisher's exact probability test, p = 0.04 and Kruskal–Wallis, p = 0.012), at the SAR-value of 12 mW/kg (Mann–Whitney, p = 0.007) and with a trend of increased albumin extravasation also at the SAR-values of 0.12 mW/kg and 120 mW/kg. There was a low, but significant correlation between the exposure level (SAR-value) and occurrence of focal albumin extravasation (r_s = 0.33; p = 0.04).The present findings are in agreement with our earlier studies where we have seen increased BBB permeability immediately and 14 days after exposure. We here discuss the present findings as well as the previous results of altered BBB permeability from our and other laboratories.     

Impact of Pregnancy and Vaginal Delivery on the Passive and Active Mechanics of the Rat Vagina

Remodeling of vaginal extracellular matrix and smooth muscle likely plays a critical role in reducing the risk of maternal injury during vaginal delivery by altering the mechanical properties to increase distension and reduce stress. Long-Evans rats were divided into five groups to examine the passive mechanical and active contractile properties throughout pregnancy and postpartum: virgin (n = 17), mid-pregnant (Day 14–16, n = 12), late-pregnant (Day 20–22, n = 14), immediate postpartum (0–2 h after delivery, n = 14), and 4 week postpartum (n = 15). Longitudinal sections of vaginal tissue were loaded to failure uniaxially for passive mechanical or active contractile properties were examined. For passive mechanics, the tangent modulus decreased 45% by mid-pregnancy and immediately postpartum (p < 0.001). The ultimate strain continuously increased up to 43% higher than virgin animals (p = 0.007) in the immediate postpartum group. For active mechanics, the maximal contractile force was 36–56% lower through immediate postpartum animals, and was significantly more sensitive to K⁺ throughout pregnancy and postpartum (p = 0.003). The changes observed in the passive and active properties of the rat vagina are consistent with what would be expected from a tissue that is remodeling to maximize its ability to distend at the time of vaginal delivery to facilitate passage of the fetus with minimal injury.     

Effect of Salvia Miltiorrhizae on the Expressions of TLR4 Protein in the Liver of Rats with SAP or OJ

To investigate the effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with severe acute pancreatitis (SAP) and obstructive jaundice (OJ), and explore the protective mechanism of salvia miltiorrhizae on the liver of rats. A total of 288 mice was used in SAP- (n = 108) and OJ-associated experiments (n = 180). The rats were randomly divided into sham-operated, model control and treated group. Based on the different time points after operation, these groups were subdivided into 3, 6 and 12 h subgroups (SAP rats, n = 12) or 7, 14, 21 and 28 days subgroups (OJ rats, n = 15). At the corresponding time points after operation, blood and liver specimens were collected to determine the contents of endotoxin and TNF-α in the blood as well as the expression levels of TLR4 protein in the liver. Compared with the corresponding model control group, though the number of dead SAP or OJ rats in the treated group declined, no statistical difference was noted; The levels of plasma endotoxin in SAP (at 6 and 12 h) or OJ rats in the treated group decreased significantly (P < 0.001 and P < 0.01, respectively); The levels of serum TNF-α in SAP (at 12 h) or OJ rats (on 14 days) declined (P < 0.001 and P < 0.01, respectively); The staining intensity as well as the product of staining intensity and positive rate of TRL4 protein only significantly declined on 7 and 28 days in OJ rats (P < 0.01). On 7 days, treated group in positive rate of TLR4 protein were significantly lower than that in model control group (P < 0.01). The pathological changes in different treated groups of SAP and OJ rats were improved. Salvia miltiorrhizae is able to reduce the levels of plasma endotoxin and inhibit effectively the expressions of TLR4 protein in the liver of SAP or OJ rats, thereby decreasing inflammatory reaction and exerting protective effect on liver function. We claimed that this paper was original and would not have any financial interest in a company or its competitor, and that all authors meet criteria for authorship. We abided the ethics in this animal experiment study. The ethics committee approval of our hospital and Zhejiang Univeristy were secured for the animal study reported, and all rats have not been abused and executive mercy killing when the observing time in this study was over.     

Effects of acetylsalicylic acid and celecoxib on the N-nitrosodiethylamine induced carcinogenesis in rat liver and esophagus

The effects of nonsteroid antiinflammatory drugs (acetylsalicylic acid and celecoxib) on N-nitrosodiethylamine-induced carcinogenesis in the liver and esophagus were studied in rats. The inhibitory effect of celecoxib on carcinogenesis was more pronounced (in comparison with acetylsalicylic acid), which manifested in a significantly decreased incidence of neoplastic changes in the liver tissue (from 91.7 to 65.2%), number of tumors in the esophagus (from 4.13 to 2.61 tumor/rat), and in delayed malignization in the liver and esophagus. The incidence of erosions and ulcers of the gastric mucosa was significantly lower after celecoxib treatment. These data indicate that celecoxib inhibits N-nitrosodiethylamine-induced carcinogenesis in the liver and esophagus. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 1, pp. 93–96, January, 2007     

Importance of the renin–angiotensin system in the regulation of arterial blood pressure in conscious mice and rats

Aim: The present experiments were designed to determine the mechanism(s) for increased sensitivity to blockade of the renin–angiotensin system in mice in comparison with rats. Methods: Mice and rats, with indwelling femoral arterial and venous catheters, were chronically administered angiotensin II or pharmacological inhibitors of the renin–angiotensin system as sodium intake was altered. Results: Increasing sodium intake led to suppression of circulating renin, angiotensin II, and aldosterone in rats and mice in the absence of alterations in arterial blood pressure. Additional experiments demonstrated that continuous intravenous infusion of angiotensin II (20 ng kg^?1 min^?1) significantly increased arterial blood pressure by approximately 35 mmHg in conscious rats at all levels of sodium intake (n = 6). In contrast, arterial pressure was unaffected by angiotensin II infusion in conscious mice under conditions of low sodium intake, although arterial pressure was increased by 16 mmHg when mice were administered a high sodium intake while infused with angiotensin II (n = 6). In comparison, blockade of the endogenous renin–angiotensin system led to significantly greater effects on arterial pressure in mice than rats. Continuous infusion of captopril (30 μg kg^?1 min^?1) or losartan (100 μg kg^?1 min^?1) resulted in a 55–90% greater fall in blood pressure in conscious mice in comparison with conscious rats. Conclusion: The present studies indicate that arterial pressure in mice is more dependent upon the endogenous renin–angiotensin system than it is in rats, but mice are more resistant to the hypertensive effects of exogenous angiotensin II.     

Effect of chronic electrical stimulation and β-GPA diet on GLUT4 protein concentration in rat skeletal muscle

The present study investigated whether alterations in the muscle high energy phosphate state initiates the contraction-induced increase in skeletal muscle GLUT4 protein concentration. Sprague-Dawley rats were provided either a normal or a 2% β-guanidinoproprionic acid (β-GPA) diet for 8 weeks and then the gastrocnemius of one hind limb was subjected to 0, 14 or 28 days of chronic (24 h day^?1) low-frequency electrical stimulation (10 Hz). The β-GPA diet, in the absence of electrical stimulation, significantly reduced ATP, creatine phosphate, creatine and inorganic phosphate and elevated GLUT4 protein concentration by 60% without altering adenylate cyclase activity or cAMP concentration. Following 14 days of electrical stimulation, GLUT4 protein concentration was elevated above non-stimulated muscle in both groups but was significantly more elevated in the β-GPA group. Concurrent with this greater rise in GLUT4 protein concentration was a greater decline in the high energy phosphates and a greater rise in cAMP. After 28 days of electrical stimulation, GLUT4 protein concentration and cAMP stabilized and was not different between diet treatments. However, the high energy phosphates were significantly higher in the normal diet rats as opposed to the β-GPA rats. These findings therefore suggest that a reduction in cellular energy supply initiates the contraction-induced increase in muscle GLUT4 protein concentration, but that a rise in cAMP may potentiate this effect.     

Effect of a milk diet on rat gastric mucosa: Receptor activity,histamine metabolism and ultrastructural analyses

A bovine milk diet (BM) resulted in remarkable changes in histamine H₂ receptor activity (sensitization) and PGE₂ receptor activity (desensitization) in gastric glands isolated from adult rats. In contrast, the receptor-cAMP systems sensitive to glucagon(s) and secretin in parietal cells and muco-peptic cells were unaffected. In the two experimental groups, cimetidine produced a parallel displacement of the histamine dose-response curve, suggesting competitive inhibition between this classical H₂ receptor antagonist and histamine. The BM diet reduced the histidine decarboxylase activity in rat gastric mucosa; the histamine content was not significantly different in control and BM-fed rats. There was no alteration of the circadian rhythm of the parietal cell (ultrastructural changes: microvilli, tubulovesicles) determined at intervals of 6 hours in milk-fed rats.Prostaglandins and other components in milk (EGF, somatostatin, etc.) might therefore protect gastric mucosa by a differential control of PGE₂ and histamine H₂ receptor activity, eitherdirectly (PGE₂ and EGF in milk) orindirectly (inhibition of endogeneous histamine synthesis/release and stimulation of prostaglandin synthesis/release).