Equal Volume Of Saline Research Articles

The effects of dexmedetomidine administered at various times on acute lung injury in rats.

To investigate the effects of dexmedetomidine (Dex) treatment administered at various times on acute lung injury (ALI). Thirty Wistar rats were randomly divided into five groups (n = 6/group). Lipopolysaccharide (LPS) was intraperitoneally injected into the rats in the LPS, Dex1, Dex2, and Dex3 groups to induce ALI, while the control group (C) was left untreated. Rats in the Dex1 group were intraperitoneally administered with 50 µg/kg Dex 30 minutes before modeling. Rats in the Dex2 group were injected with 25 µg/kg Dex 30 minutes before modeling and two hours after. Rats in the Dex3 group received 50 µg/kg Dex two hours after modeling. The animals in the C and LPS groups were given an equal volume of saline. The wet-to-dry (W/D) weight ratio of the rats' lungs was calculated, and pathological alterations in lung tissues were observed. The concentrations of inflammation-related factors and the expression of Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and matrix metallopeptidase 9 (MMP9) were measured. The W/D ratio, expression of inflammatory factors, and expression of JAK1, STAT3, and MMP9 were significantly increased in the ALI rats (p < 0.05) compared with the C group. The level of anti-inflammatory factors in the Dex-treated groups was also significantly increased compared with the LPS group (p < 0.05). The concentration of anti-inflammatory factors in the Dex2 group was significantly higher than that recorded in the Dex1 and Dex3 groups (p < 0.05). Dex treatment administered at different times protects rats against LPS-induced ALI to varying degrees. The protective effects of Dex were most robust when administered both before and after LPS stimulation.

Efficacy and safety of iloprost in trauma patients with haemorrhagic shock-induced endotheliopathy-Protocol for the multicentre randomized, placebo-controlled, blinded, investigator-initiated shine-trauma trial.

BackgroundTraumatic injury accounts for 800 000 deaths in the European Union annually. The main causes of deaths in trauma patients are exsanguination and multiple organ failure (MOF). We have studied >1000 trauma patients and identified shock‐induced endotheliopathy (SHINE), the pathophysiological mechanism responsible for MOF and high mortality. Pilot studies indicate that low‐dose iloprost (1 ng/kg/min) improves endothelial functionality in critically ill patients suggesting this intervention may improve patient outcome in traumatic SHINE.Material and MethodsThis is a multicentre, randomized, blinded clinical investigator‐initiated phase 2B trial in trauma patients with haemorrhagic shock‐induced endotheliopathy. Patients are randomized 1:1 to 72 hours infusion of iloprost 1 ng/kg/min or Placebo (equal volume of saline). A total of 220 trauma patients will be included. The primary endpoint is the number of intensive care unit (ICU)‐free days, within 28 days of admission. Secondary endpoints include 28‐ and 90‐day all‐cause mortality, hospital length of stay, vasopressor‐free days in the intensive care unit (ICU) within 28 days, ventilator‐free days in the ICU within 28 days, renal replacement‐free days in the ICU within 28 days, number of serious adverse reactions and serious adverse events within the first 4 days of admission.DiscussionThis trial will test the safety and efficacy of administration of iloprost vs placebo for 72 hours in trauma patients with haemorrhagic shock‐induced endotheliopathy. Trial endpoints focus on the potential effect of iloprost to reduce the need for ICU stay secondary to mitigation of organ failure.Trial registrationSHINE‐TRAUMA trial—EudraCT no. 2019‐000936‐24—Clinicaltrials.gov: NCT03903939 Ethics Committee no. H‐19014482.

Zihuai recipe alleviates cyclophosphamide-induced diminished ovarian reserve via suppressing PI3K/AKT-mediated apoptosis

Ethnopharmacological relevanceZihuai recipe (ZHR), a Chinese herbal prescription, is widely used for the clinical treatment of Diminished ovarian reserve (DOR) infertility. However, little is known regarding its underlying mechanisms of DOR treatment. Aim of the studyThis study aimed to investigate the beneficial effects of ZHR on the treatment of DOR and to reveal the underlying mechanisms. Materials and methodsSixty 8-week-old Sprague–Dawley female rats were randomly divided into the following six groups (n=10 per group): control group, DOR group, low-dose (2.7 g/kg/day) ZHR (L-ZHR) group, medium-dose (5.4 g/kg/day) ZHR (M-ZHR) group, high-dose (10.8 g/kg/day) ZHR (H-ZHR) group, and hormone replacement therapy (HRT) group. The DOR model was established in all the groups, except the control group, by a single intraperitoneal injection of 90 mg/kg cyclophosphamide (CTX). After the induction of the DOR model, rats were weighed and administered either the relevant dose of ZHR or an equal volume of saline solution (in the control and DOR groups). Rats in the HRT group received estradiol valerate tablets (0.16 mg/kg/day) for 4 days， with medroxyprogesterone acetate tablets (0.86 mg/kg/day) added on day 4. After 32 days of treatment, the rats were euthanized and the ovaries were collected for sampling. Ovarian morphology was observed by hematoxylin and eosin staining and the number of follicles was counted under a microscope. The serum levels of anti-Müllerian hormone (AMH), gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were quantified by ELISA. A TUNEL assay was used to analyze the level of apoptosis of the ovarian cells. The protein expressions of p-PI3K, p-AKT, PI3K, AKT, cleaved caspase-3, BAX, and Bcl-2 were measured by western blotting and immunohistochemistry. Data analysis was performed with SPSS 20.0 software. ResultsZHR administration increased the ovarian index and the serum levels of AMH, GnRH, and E2, while it lowered those of FSH and LH. ZHR treatment also increased the numbers of primordial, primary, secondary, and antral follicles, as well as the numbers of corpora lutea, but decreased the number of atretic follicles. Furthermore, ZHR administration decreased the percentage of TUNEL-positive ovarian cells. After treatment with ZHR, the protein expression levels of p-PI3K/PI3K, p-AKT/AKT, cleaved caspase-3 and BAX were decreased, whereas the level of Bcl-2 was increased. ConclusionsZHR improved the ovarian reserve in CTX-induced DOR rats. The mechanisms of ZHR on DOR may be mediated through the regulation of gonadal hormones of the hypothalamic-pituitary-ovarian axis, and the inhibition of PI3K/AKT-mediated apoptosis in granulosa cells.

Overexpression of the Aryl Hydrocarbon Receptor (Ahr) Mediates an Oxidative Stress Response following Injection of Fine Particulate Matter in the Temporal Cortex.

Studies have shown that particulate matter (PM) induces the expression of the aryl hydrocarbon receptor (Ahr) leading to the activation of the oxidative stress response. This study is aimed at characterizing the specific impact of fine PM on the expression profile of the Ahr and oxidative stress response in the primary auditory cortex. PM2.5 (<1.8 μm)-loaded filters were suspended in sterile saline to 102.6–111.82 μg/ml. Next, 10 μl of PM2.5 or an equal volume of saline was administered intracranially into the temporal cortex of two groups of rats (PM2.5 and control; n = 14 per group), respectively. One week after intracranial injection, the temporal cortex was harvested. Transmission electron microscopy was performed to evaluate the distribution of PM2.5 within the temporal cortex. Additionally, the mRNA and protein expression levels of cytochrome P450 1A1 (CYP1A1), CYP1B1, inducible nitric oxide synthase (iNOS), Ahr, and brevican mRNA and protein were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) or western blotting, respectively. Finally, the protein expression levels of the receptor for advanced glycation end products (RAGE) were estimated using enzyme-linked immunosorbent assay (ELISA). PM2.5 was observed in intracellular vesicles within the temporal cortex following intracranial injection. Levels of oxidative stress molecules (i.e., CYP1A1, CYP1B1, and iNOS), Ahr, Brevican, and RAGE were higher in the PM2.5 group compared with the control group. Intracranial administration of PM2.5 led to increased levels of Ahr and markers of an oxidative stress response in the temporal cortex. The oxidative stress response-mediated increases in the levels of brevican and RAGE.

Huoxin Pill () Attenuates Cardiac Fibrosis by Suppressing TGF-β1/Smad2/3 Pathway in Isoproterenol-Induced Heart Failure Rats.

To evaluate the effects of Huoxin Pill (, HXP) on cardiac fibrosis and heart failure (HF) in isoproterenol (ISO)-induced HF rats. Thirty Wistar rats were randomly divided into 5 groups including control, HF, isosorbide mononitrate (ISMN), HXP low (HXP-L), and HXP high (HXP-H) groups (n=6 for each group) according to the complete randomization method. Rats were pretreated with ISMN (5 mg/kg daily), low concentration of HXP (10 mg/kg daily) or high concentration of HXP (30 mg/kg daily) or equal volume of saline by intragastric administration for 1 week, followed by intraperitoneal injection of ISO (10 mg/kg, 14 days), and continually intragastric administrated with above medicines or saline for additional 6 weeks. The effects of HXP treatment on the cardiac function, heart weight index (HWI), pathological changes, and collagen content were further assessed. Moreover, the role of HXP on activation of transforming growth factor- β 1 (TGF-β 1)/Smads pathway was further explored using immunohistochemistry (IHC) and Western-blot assay. HXP treatment significantly alleviated the decrease of ejection fraction (EF) and fractional shortening (FS), while decreased the elevation of left ventricular end-systolic volume (LVESV) in ISO-induced HF rats (P<0.05). Moreover, HXP treatment obviously attenuated the increase of HWI and serum level of creatine kinase MB (CK-MB, P<0.05), as well as pathological changes in ISO-induced HF rats. Further determination indicated that HXP treatment alleviated the elevation of collagen I and collagen III protein expression in cardiac tissues of ISO-induced HF rats. Furthermore, HXP treatment significantly down-regulated the increase of TGF-β 1 and p-Smad2/3 protein expression in cardiac tissues of HF rats (P<0.05), while did not affect the expression of total Smad2/3. HXP attenuated heart failure and cardiac fibrosis in ISO-induced HF rats by suppression of TGF-β 1/Smad2/3 pathway.

Shexiang Baoxin Pill Attenuates Ischemic Injury by Promoting Angiogenesis by Activation of Aldehyde Dehydrogenase 2.

Promoting angiogenesis is a critical treatment strategy for ischemic cardiovascular diseases. Shexiang Baoxin Pill (SBP), a traditional Chinese medicine, has been reported to be capable of relieving angina and improve heart function by promoting angiogenesis. The aim of this study was to determine the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in SBP-induced angiogenesis. Left femoral artery ligation was performed in wild-type mice (WT) and ALDH2 knockout mice, which were administrated with SBP (20 mg/kg/d) or equal volume saline per day by gastric gavage for 2 weeks. Perfusion recovery, angiogenesis in chronic hind limb ischemia, was significantly improved in the WT + SBP group than in the WT group. However, these beneficial effects were absent in ALDH2 knockout mice. In vitro, hypoxia impaired the ability of proliferation, migration and tube formation, sprouting angiogenesis, and promoted apoptosis in cardiovascular microvascular endothelial cells, whereas the hypoxia damage was restored by SBP. The protective effect of SBP was remarkably weakened by ALDH2 knockdown. Furthermore, SBP suppressed hypoxia-induced ALDH2/protein kinase B (AKT)/mammalian target of rapamycin pathways. In conclusion, this study demonstrated that SBP protected lower limb from ischemia injury through the ALDH2-dependent pathway. The protective mechanism of SBP in cardiovascular microvascular endothelial cells was partly mediated through ALDH2/AKT/mammalian target of rapamycin pathways.

Neurological consequences of exercise during prenatal Zika virus exposure to mice pups

Purpose/Aim Zika virus (ZIKV) infection during the pregnancy period is related to microcephaly and neurobehavioral disorders at birth, while prenatal exercise is supposed to provide neuroprotection in newborns pups. The aim of this study was to investigate the neurological consequences of exercise during prenatal ZIKV exposure to mice pups. Material and methods Twelve weeks female mice were randomly assigned into three groups: Control group, intraperitoneally injected with saline (Control); untrained group, intraperitoneally injected with ZIKV (ZIKV); and trained group, intraperitoneally injected with ZIKV (ZIKV/swim). There was one familiarization week prior to the beginning of the swimming training. Dams swam for 60 min/session, 5 days/week, during 4 weeks. Mating occurred between the fifth and seventh day of the first week of the swimming training. ZIKV 106 plaque-forming units/100 µl (106 PFUs/100 µl) or an equal volume of saline was intraperitoneally injected in the pregnant mice at embryonic day 10.5. Pup’s body mass and brain weight were measured at postnatal day 1 (P1). Behavioral tests were performed from P30 to P35. Thereafter, hippocampal levels of syntaxin-1, GFAP, IBA-1, and BDNF were measured. Results Exercise during prenatal ZIKV exposure prevented brain atrophy, development of depression, anxiety, and disruption of social behavior. Exercise during prenatal ZIKV exposure inhibited the overexpression of microglia (IBA-1) and astrocytes (GFAP), with reduction of BDNF levels in the hippocampi of female and male mice pups. No significant changes were seen in syntaxin-1 levels. Conclusion Our findings reveal beneficial effects of exercise during pregnancy exposure to ZIKV in mice pups.

The effects of doxapram on haematology, serum biochemical parameters and erythrocyte oxidant/ antioxidant status in dogs anaesthetized with propofol.

The present prospective randomized experimental study was designed to determine the effects of doxapram on haematological, serum biochemical and antioxidant status in dogs after propofol anaesthesia. Twenty‐four healthy male mixed breed dogs, aged 1–2 years, weighing 20.4 ± 2.6 kg was studied. Each dog was anaesthetized twice, with at least one week for washout. Animals were sedated with acepromazine (0.1 mg/kg) intramuscularly. Forty minutes later, anaesthesia was induced using intravenous (IV) propofol (4 mg/kg) titration and maintained for 30 min by propofol (0.2 mg kg−1 min−1). After propofol was discontinued, doxapram (2 mg/kg) hydrochloride was administrated IV in PD treatment while an equal volume of saline was administrated in PS treatment. Blood parameters were analysed in four times: immediately before sedation (T1), after treatment (T2), after complete recovery (T3) and 24 hr later (T4). Haematological assessments revealed no significant difference between treatments except in haematocrit which was significantly reduced at T4 (24 hr later) in PD. A decreasing trend of all haematological variables was observed after doxapram administration until recovery, except monocyte, mean corpuscular haemoglobin, red blood cell distribution width and platelet count. Serum urea, creatinine, glucose, cholesterol, direct bilirubin concentration and alanine aminotransferase activity were not changed following doxapram administration compared to the PS treatment. After doxapram administration, Creatinine (T3), Albumin (T2) and Protein (T2 & T3) decreased while Glucose (T2 & T3) and BT (T3) increased. Antioxidant parameters measured showed no difference between treatments or time. Doxapram (2 mg/kg) IV did not induce any major negative effects on haematological, serum biochemical variables and oxidant/antioxidant status in dogs after propofol anaesthesia.

BALB/c female subjected to valproic acid during gestational period exhibited greater microglial and behavioral changes than male mice: A significant contra intuitive result.

Most animal model studies of autism spectrum disorders (ASD) were performed in males. Thus, little is known about the mechanisms underlying disease progression in females. Here, we searched for potential influences of sex and environment on gestational valproic acid-induced behavioral abnormalities using hippocampal-dependent tasks, and on number and morphometry of microglia of the molecular layer of the dentate gyrus (Mol-DG). We compared male and females BALB/c control mice with BALB/c mice gestationally exposed to VPA with regards to exploratory activity and risk assessment in novel environments. Pregnant females and males on gestational day 12.5 received VPA in saline (600mg/kg body weight) or an equal volume of saline by gavage. After weaning, female and male offspring were housed separately either in standard laboratory cages (SE) or enriched cages (EE). At 5months of age, these mice underwent behavioral testing and had their brains processed for microglia IBA1 immunolabeling. Compared with control mice, VPA-exposed mice exhibited abnormal behavior in exploring novel environments and assessing risk, and these effects were significantly greater in females than in males and less intense among mice from enriched cages. Three-way ANOVA revealed that environment, sex and valproic acid conditions interacted and altered the behavior results. Microglia number and volume of the Mol-DG were significantly higher in VPA-exposed groups raised in standard cages. The results of counting the intersects of microglia branching on Sholl's circles analyzed with permutational MANOVA, demonstrated that in comparison with males, there was a greater reduction in the number of intersections in females raised in standard cages. These findings suggest that the increased microglia and morphological changes might be associated with behavioral dysfunction in ASD. Moreover, the somatomotor and cognitive stimulation of environmental enrichment started at weaning may be beneficial for reducing behavioral abnormalities and reduction of microglia response in adulthood.

Cerebral blood flow and oxygenation in rat brain after soman exposure

Nerve agent exposure can cause debilitating neurological damage even with treatment. Currently accepted treatments involve attenuating the cholinergic crisis and seizure onset but do not focus directly on neuroprotection. Hence, there is a need for improved treatments to reduce neurological deficits. It is important to understand the pathophysiology of nerve agent mediated injury in order to identify effective treatment targets. Nerve agent-induced seizures are believed to be the main contributor to the neuropathology. Recently seizures have been shown to cause vascular changes that may actually attenuate neurological damage. This study evaluated the effect of soman-induced convulsive seizures on the relationship between CNS oxygen consumption and supply.To simultaneously assess changes in oxygenation and perfusion, rats were implanted with permanently fixed fiber-optic tissue oxygen sensing probes in the motor cortex and imaged with continuous arterial spin labelling MRI to measure cerebral blood flow. Baseline tissue oxygen tension (ptO2) and cerebral blood flow (CBF) were measured in isoflurane anaesthetized rats at least one day prior to soman or saline exposure. Rats were pretreated with HI-6 dimethansulfonate and atropine methyl nitrate (125 mg/kg and 20 mg/kg; intraperitoneal) followed by a convulsive dose of soman (90 μg/kg; subcutaneous) or equal volume of saline. Three additional treatments of HI-6/AMN were administered to improve survival. At 1.5 -hs after exposure, ptO2 and cerebral blood flow measurements were conducted.There was a significant decrease in CBF 1.5 -hs following soman exposure but no change in ptO2 was found. When we correlated ptO2 and CBF, for a given ptO2, there was lower CBF following soman exposure. This may indicate metabolism is inhibited, possibly because of mitochondrial impairment, therefore reducing oxygen demand. These data show hypoperfusion in brain following soman exposure which would be expected to contribute to soman-related neuropathology.

Methylene blue reduces incidence of early postoperative cognitive disorders in elderly patients undergoing major non-cardiac surgery: An open–label randomized controlled clinical trial

Study objectiveThe purpose of the present study was to investigate whether methylene blue (MB) could reduce the incidences of postoperative delirium (POD) and early postoperative cognitive dysfunction (POCD) in elderly patients undergoing major non-cardiac surgery. DesignProspective, randomized, open–label clinical trial. SettingUniversity-affiliated hospital. PatientsTwo hundred and forty-eight elderly patients scheduled for non-cardiac surgery. InterventionsElderly patients undergoing non-cardiac major surgery were randomly assigned to MB group (n = 124), who receiving intravenous infusion of 2 mg/kg MB within 60 min immediately after anesthetic induction, or control group (n = 124), who receiving equal volume saline in the same way. MeasurementsAll patients were evaluated with delirium and neuropsychological batteries before and after surgery, as well as perioperative adverse events. Two plasma biomarkers superoxide dismutase (SOD) and homocysteine (HCY) were measured pre- and post-operatively. Main resultsThere were total 39 cases(15.7%)experienced POD. The incidence of POD in MB group was significantly less than that in control group (7.3% vs. 24.2%, OR = 0.24, 95%CI: 0.11–0.53, p < 0.001). The incidence of early POCD at postoperative 7th day in MB group was also less than that in control group (16.1% vs. 40.2%, OR = 0.30, 95% CI: 0.16–0.57, p < 0.001). The adverse events were comparable in both groups. In addition, there was no significant correlation between POD/POCD and levels of SOD or HCY. ConclusionWe conclude that intraoperative intravenous 2 mg/kg MB could significantly reduce the incidences of POD and early POCD in elderly surgical patients, while not remarkably increase incidence of perioperative adverse events, suggesting MB may be clinically effective and safe for prevention of early postoperative neurocognitive disorders.

Recombinant thrombomodulin alleviates oxidative stress without compromising host resistance to infection in rats infected with methicillin-resistant Staphylococcus aureus

Recombinant thrombomodulin (rTM) has been used for treatment of sepsis-associated disseminated intravascular coagulation. Recent studies have suggested that anticoagulant therapy might dampen the protective role of immunothrombosis. We examined if rTM might worsen infectious diseases. Male Sprague–Dawley rats with jugular-vein catheterization were divided into three groups: no anticoagulation; rTM pretreatment; rTM treatment at 6 h. Live methicillin-resistant Staphylococcus aureus (MRSA) was inoculated into the tail vein of rats. rTM was administered into the jugular-vein catheter before or 6 h after MRSA inoculation, while an equal volume of saline was administered in the no-anticoagulation group. Blood samples were collected from the jugular-vein catheter before, 6 h and 12 h after MRSA inoculation. Tissue samples were collected from anesthetized rats when moribund or 18 h after MRSA inoculation. The survival rate of rats in the no-anticoagulation group, rTM pretreatment group, and rTM treatment at 6-h group was 50%, 25%, and 75%, respectively. Bacterial burden in blood, lung, liver, and spleen was neither increased nor decreased in rats treated with rTM. The ratio of bacteria found in the extravascular space to those in the intravascular space was increased in rats treated with rTM although the statistical power for this was low because of the small sample size. Metabolomics analysis revealed that rTM treatment alleviated oxidative stress, as evidenced by the decrease in levels of oxidized glutathione with reference to reduced glutathione. rTM did not promote bacterial propagation but alleviated oxidative stress in our rat model of bloodstream infection with MRSA. Further large-scale studies are needed to confirm these findings.

6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT3 Receptor System in Rats.

Purpose[6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol’s antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT3 receptor), in a cisplatin-induced pica model of rats.MethodsRats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT3 receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively.Results[6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol.ConclusionThis suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT3 receptor system.

The Possible Inhibition Effect of Lycium barbarum Polysaccharides on Rat Intracerebral Hemorrhage Secondary Neuronal Apoptosis through Intervening Endogenous/Exogenous Pathways of Apoptosis

AbstractObjective The aim of this study was to explore the inhibition effect and possible mechanism of Lycium barbarum polysaccharides (LBP) on rat intracerebral hemorrhage (ICH) secondary neuronal apoptosis.Materials and Methods High-, medium-, and low-dose LBP (50, 100, and 200 mg•kg) and nimodipine (10 mg•kg) groups were given once daily by 15-day gavage before operation, while the sham operation and ICH groups were given the equal volume of saline. An ICH model was established by autologous blood injection and the neurological function in each group was scored at 4, 8, 12, 24, and 48 hours after modeling. Furthermore, terminal deoxynucleotidyl transferase dUTP nick end labeling analysis was performed to detect neuronal apoptosis, while western blot, immunohistochemistry, and real-time-polymerase chain reaction were used to study the influence of LBP on ICH secondary neuronal apoptosis.Results The neurological function score was significantly decreased after ICH, and the intervention effect of a single drug was not evident. The apoptotic nerve cells increased significantly in the ICH group but decreased considerably in the LBP groups. Furthermore, tumor necrosis factor alpha (TNF-α) expression decreased significantly, while B-cell lymphoma 2 expression increased substantially in the high- and medium-dose LBP groups compared with ICH group, suggesting that LBP could reduce the effect of ICH. However, the impact of LBP did not correlate positively with the dose.Conclusion The application of LBP may not significantly improve neurological function after ICH, but it can inhibit rat ICH secondary neuronal apoptosis.

Individual Subnuclei of the Rat Anterior Thalamic Nuclei Differently affect Spatial Memory and Passive Avoidance Tasks

The role of the anterior thalamic nuclei (ATN) has been proven in different learning and memory tasks. The ATN consist of three main subnuclei, the anterodorsal (AD), anteroventral (AV) and anteromedial (AM), which have different biological characteristics such as distinct circuitry, cell population and neurotransmitter content. The role of ATN subnuclei in learning and memory has been shown in several studies. However, their probable role in different phases of memory including acquisition, consolidation and retrieval are not still well-known. For this purpose, the effect of reversible inactivation of each ATN subnucleus on different memory phases in two behavioral tasks including passive avoidance (PA) and Morris water maze (MWM) was studied. Wister male rats were bilaterally implanted with cannulas above the AD, AV or AM subnucleus in separate experimental groups in order to inject lidocaine (4%) for their temporal inactivation or, equal volume of saline. Animals were trained in the behavioral tasks and different phases of memory were investigated. Our findings indicated that the AV inactivation strongly disrupts all memory phases in the MWM, and consolidation and retrieval phases in the PA tasks. The AM inactivation had no effect on acquisition of both tasks while it impaired the PA consolidation and MWM retrieval. However, the AD inactivation could not disrupt memory phases in the PA task but impaired the MWM retrieval. In conclusion, it seems that the ATN distinct subnuclei differently affect different phases of memory in these two tasks.

Assessment of the safety of intravitreal injection of metoprolol tartrate in rabbits.

To verify the safety of different doses of intravitreal metoprolol tartrate (MT) after intravitreal injection in rabbit eyes. Animals were randomly assigned into 2 groups: group I received 50µg of MT and group II 100µg of MT. A volume of 0.05mL of the drug solution was administered through an intravitreal injection, while the control eyes received an equal volume of saline solution. Safety was assessed by clinical observation, electroretinography (ERG) and histological evaluation. No evidence of clinical toxicity was observed. ERG waveforms from the MT treated eyes were similar to those recorded from the control eyes in dark-adapted state, amplitude and the implicit time are similar between the groups in light-adapted state, and their retinas had no signs of toxicity by histological evaluation 7days after intravitreal injection. The intravitreal use of metoprolol at 50 and 100µg dosages does not cause short-term retinal toxicity in rabbits.

Evaluation of intramuscular injection of oxytetracycline for use as an experimental model to induce pain and assess the efficacy of pain mitigation strategies in dairy cows.

To evaluate IM injection of oxytetracycline as an experimental model to induce pain and assess the analgesic efficacy of flunixin meglumine (FM) in dairy cows. 15 healthy nonlactating Jersey (n = 10) and Holstein (5) cows. In the first of 2 experiments, 5 Jerseys were administered oxytetracycline (10 mg/kg, IM), divided between the right side of the neck and left hind limb. The left side of the neck and right hind limb received sham injections. Cows were also randomly assigned to receive FM (2.2 mg/kg, IV; n = 3) or an equal volume of saline (0.9% NaCl) solution (0.044 mL/kg, IV; control; 2) once daily for 5 days. The mechanical nociceptive threshold (MNT) was measured before oxytetracycline administration and at predetermined times after each injection of the assigned treatment. Experiment 2 was similar to experiment 1 except it involved 5 Jerseys and 5 Holsteins, oxytetracycline was injected only in a hind limb, and the assigned treatment was administered for 10 days. For both experiments, mean MNT for the oxytetracycline injection site was consistently less than that for the sham injection site in the hind limbs, and mean MNT at the hind limb oxytetracycline injection site for FM-treated cows was greater than that for control cows beginning on day 3. IM injection of oxytetracycline in a hind limb reliably induced signs of pain in dairy cows and, with validation, might be useful as an experimental model for assessing pain mitigation strategies in cattle.

P0519HEXARELIN PROTECTS ISCHEMIA REPERFUSION INDUCED ACUTE KIDNEY INJURY BY TARGETING 14-3-3Σ

Abstract Background and Aims Acute kidney injury (AKI), manifested as a sudden decline in renal function on the order of days or a week, is one of the most common complications and is strongly associated with renal prognosis, medical expenses and length of stay of hospitalized patients. However, incidence of AKI can be reduced by early intervention. Hexarelin is a synthetic analogue of ghrelin with a potent GH releasing activity, which is also found to exhibited a significant protectant activity against postischemic ventricular dysfunction in isolated perfused hearts subjected to low flow ischemia and reperfusion. This study aims to explore the effects of hexarelin on ischemia reperfusion induced acute kidney injury (I/R-AKI) and the underlying mechanism of it. Method Thirty healthy male SPF SD aged at 8 weeks weighing 250-300g rats were divided into 5 groups including normal group, sham operation group, acute kidney injury (AKI) group, acute kidney injury group after hexarelin (HEX + AKI), and acute kidney injury group after saline (Saline + AKI). Bilateral kidney artery clamping was applied for 50 min to induce AKI. The drug-administered group and the saline-controlled group rats were treated with intraperitoneal injections 7 days before modelling and the Hex + AKI group and the saline + AKI group were given Hexarelin (dose 100 μg/kg. d) and equal volume of saline, respectively. To explore the underlying mechanism of HEX on I/R-AKI, gene expression profiling of AKI samples were searched from Pubmed, GEO dataset. Differential expression genes were used to predict canonical signal transduction pathways and signalling networks. Molecular docking was used to predict the combination of hub proteins and HEX. Results 1) Renal function in HEX-pretreated rats was significantly improved compared with control group: HE results showed that renal tubules were less dilated and rebuilt after pretreatment, and the infiltration area was significantly reduced; serum creatinine (P = 0.0005 &amp;lt;0.05), urea nitrogen (P &amp;lt;0.0001) concentration were significantly reduced; RT-qPCR showed that relative expression of Kim-1 (P&amp;lt;0.0001), caspase3 (P = 0.007), Bax (P &amp;lt;0.0001), Bad (P = 0.0168 &amp;lt;0.05) in HEX+AKI group were significantly decreased while the relative expression of Bcl-2 (P &amp;lt;0.05) was significantly increased compared with saline treated rats; 2) Microarray data analysis showed that 63 differential expression genes including SFN, Cyr61, Kim-1 were hub genes in the development of I/R-AKI; 3) Three-dimensional structure of the hub proteins HEX were obtained from the SWISS-MODEL database and the PubChem compound database, and Autodock software was used to calculate the molecular docking between proteins and HEX. Results showed that HEX and the protein that encoded by the gene SFN (SFN, 14-3-3σ) binding stably with a binding energy of -8.51; Conclusion Hexarelin protects ischemia reperfusion induced acute kidney injury by targeting 14-3-3σ.

P0528RENOPROTECTIVE EFFECT OF IL-34 INHIBITION ON CISPLATIN-INDUCED NEPHROTOXICITY IN MICE

Abstract Background and Aims Interleukin (IL)-34, a macrophage (Mø) mediator, is expressed by tubular epithelial cells (TECs). However, the influence of IL-34 on TECs injury has not been fully elucidated. We investigated the physiological properties of IL-34 on TECs damage caused by cisplatin-nephrotoxicity (CP-N). Method 7-week-old male C57BL/6 (B6) mice (n=16) were fasted for 8 hours and then induced CP-N by intraperitoneal injection (IP) of CP (25 mg/kg) on day 0. Groups of animals were given either anti-mouse IL-34 antibody (CP+anti-IL-34 Ab, 400 ng/kg, n=8) or vehicle (CP+V, equal volume of saline, n=8) daily by IP from day -1 to day 2. Three age-matched male B6 mice were used as normal control (NC). All mice were sacrificed on day 3. In addition, mouse renal proximal TECs (MRTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis. Cells were stimulated with CP (2 μg/mL), then treated with or without anti-IL-34 Ab (1000 pg/mL). Results Compared to the NC, CP+V mice exhibited marked acute kidney injury (AKI) and upregulated expression of IL-34 and its two receptors, cFMS and PTP-ζ. Compared to the vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the intrarenal expression levels of IL-34 and its two receptors in CP-N mice; it also significantly suppressed serum IL-34 levels (72.1 ± 5.6 vs. 40.4 ± 7.5 pg/mL, p=0.013). Additionally, treatment with anti-IL-34 Ab significantly improved serum Cr levels (1.3 ± 0.2 vs. 0.7 ± 0.1 mg/mL, p=0.033), ameliorated tubulointerstitial injury (numbers of casts/HPF: 11.9 ± 2.6 vs. 6.5 ± 1.8, p=0.048), and suppressed the number of F4/80+ Mø (17.5 ± 2.7 vs. 11.1 ± 1.1/HPF, p=0.041) and TUNEL+ apoptotic cells (29.2 ± 4.9 vs. 16.7 ± 2.7/HPF, p=0.036) in CP-N mice. The renal cortical transcript levels of Kim-1, MIP-1/CCL3, TNF-α, and Bax were significantly lower in the CP+anti-IL-34 Ab mice than in the CP+V mice. Furthermore, the CP+anti-IL-34 Ab mice showed significantly less renal infiltration of CD11b+F4/80+TNF-α+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its two receptors in MRTEpiC. Treatment with anti-IL-34 Ab significantly suppressed CP-induced caspase-3 and Bax expression with degradation of ERK1/2 phosphorylation in the damaged MRTEpiC. Conclusion IL-34 secreted from damaged TECs was involved in the progression of CP-N. Inhibition of IL-34 with neutralizing antibody directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK1/2. Blocking of IL-34 might suppressed proliferation of cytotoxic Mø, which indirectly led to the attenuation of CP-N. Thus, IL-34 represents a potential as therapeutic target for AKI with TECs injury.

N-acetylcysteine maintains penile length and erectile function in bilateral cavernous nerve crush rat model by reducing penile fibrosis.

Penile length shortening and erectile dysfunction are common complications after radical prostatectomy. Various methods have been used to maintain erectile function, but less attention has been paid to preserving penis length. N-acetylcysteine (NAC) has the effect of antioxidation and antifibrotic, which may be beneficial to improve those postoperative complications. This study investigated the effect of NAC on maintaining the penile length and the erectile function after bilateral cavernous nerve crush (BCNC) and its underlying mechanism. Twenty-four male rats were randomly divided into three groups: control group, BCNC group, and BCNC + NAC group. NAC or equal volume of saline was daily administrated by intragastric gavage for 4 weeks. The initial and end penile lengths were measured. Intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio was calculated to assess erectile function. Hematoxylin–eosin staining, Masson's trichrome staining, immunohistochemistry, and Western blot were performed to explore cellular and molecular changes of the penis. Compared to the BCNC group, the penile length, ICP/MAP ratio and smooth muscle/collagen ratio in the BCNC + NAC group were improved significantly (all P < 0.05), and the expressions of endothelial nitric oxide synthase, α-smooth muscle actin, glutathione, and glutathione peroxidase 1 were significantly increased after NAC treated (all P < 0.05), along with the decreased expressions of hypoxia-inducible factor-1α, transforming growth factor-β1, collagen I, collagen III, collagen IV, malonaldehyde, and lysine oxidase (all P < 0.05). This study demonstrated that NAC could maintain penile length and partly improve erectile function. Possible mechanism is directly and/or indirectly related to antihypoxic and antifibrosis.