Acute Model Research Articles

Neuroprotective role of epigallocatechin-3-gallate in acute glaucoma via the nuclear factor-κB signalling pathway.

Glaucoma is a disease involving impaired visual function accompanied by degeneration and necrosis of the optic nerve. Epigallocatechin-3-gallate (EGCG) exerts a neuroprotective effect against the degeneration of retinal ganglion cells. However, whether EGCG can relieve glaucoma and the possible mechanisms remain unclear. In order to determine the function of EGCG in glaucoma, an acute glaucoma rat model was established. Optic neuropathology was examined by haematoxylin-eosin staining and immunofluorescence staining for class III-β tubulin. The levels of inflammation-associated cytokines, such as interleukin (IL)-4, IL-6, TNF-α, IL-1β, IL-13 and IFN-γ were measured by flow cytometry. T cell proliferation was assessed by the carboxyfluorescein diacetate succinimidyl ester method. Finally, the functional role of EGCG in glaucoma was explored. The levels of the inflammation-associated proteins p-IκBα and p-p65 were measured by western blot analysis. The results showed that optic nerve injury occurred, and elevated levels of the inflammatory cytokines IL-4, IL-6, TNF-α, IL-1β, IL-13 and IFN-γ were observed in the rat model of acute glaucoma. In addition, an increased T lymphocyte proliferation rate and imbalance of Th1/Th2 cytokines were present in the models. Importantly, treatment with EGCG significantly alleviated optic nerve injury. At the molecular level, EGCG decreased the levels of inflammation-associated cytokines, decreased the proliferation rate of T lymphocyte cells, and repaired the imbalance of Th1/Th2 cytokines. Moreover, EGCG inhibited the increase in the phosphorylation of IκBα and p65 caused by modelling and thus suppressed the activation of the nuclear factor (NF)-κB signalling pathway. The findings of the present study indicate that EGCG could attenuate the symptoms of glaucoma and inhibit inflammatory responses by suppressing the NF-κB signalling pathway in a rat glaucoma model.

Identification of 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1H)-one APJ receptor agonists

Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr1]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr1]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr1]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.

Mechanism of paeonol combined with paeoniflorin against myocardial ischemia injury:based on proteomics

The study aims to investigate the effect of the compatibility of paeonol and paeoniflorin(hereinafter referred to as the compatibility) on the expression of myocardial proteins in rats with myocardial ischemia injury and explore the underlying mechanism of the compatibility against myocardial ischemia injury. First, the acute myocardial infarction rat model was established by ligation of the anterior descending branch of the left coronary artery. The model rats were given(ig) paeonol and paeoniflorin. Then protein samples were collected from rat cardiac tissue and quantified by tandem mass tags(TMT) to explore the differential proteins after drug intervention. The experimental results showed that differential proteins mainly involved phagocytosis engulfment, extracellular space, and antigen binding, as well as Kyoto encyclopedia of genes and genomes(KEGG) pathways of complement and coagulation cascades, syste-mic lupus erythematosus, and ribosome. In this study, the target proteins and related signaling pathways identified by differential proteomics may be the biological basis of the compatibility against myocardial ischemia injury in rats.

Effects of β3-adrenoceptor agonist on acute urinary retention in a rat model.

To investigate the protective effect of mirabegron on bladder dysfunction in an acute urinary retention rat model. Thirty-six 16-week Sprague-Dawley rats were assigned to the mirabegron and normal saline (N/S) groups. Each group of eighteen was divided into sub-groups of 6 for 30min, 2h, and 24h. They were administered mirabegron (10mg/kg) and N/S daily for 4weeks, respectively. Mirabegron and N/S groups were divided into sub-groups of 6 rats for 30min, 2h, and 24h. The changes in bladder blood flow were measured using laser Doppler (moorVMS-LDF2). Histopathological examination of the bladder and nitric oxide (NO) measurement were performed. During the urinary retention phase in the mirabegron group, it showed higher and rapider recovery of blood flow; the lowest at 19.5% ± 3.68% at 3min, a significant recovery from the lowest value as 23.7 ± 3.4% at 10min, than that in the N/S group; 15.1 ± 1.84% at 5min, 23.7 ± 3.4% at 20min, respectively (P < 0.05). At 30min, 120min, and 24h after reperfusion, the recovery of blood flow in the mirabegron group was significantly higher than that in the N/S group (mirabegron: 41.1 ± 1.7%, 59.9 ± 7.2%, and 89.7 ± 4.4%, N/S: 31.3 ± 2.1%, 47.3 ± 4.5%, 83.9 ± 3.6%, respectively (P < 0.05)). NO levels tended to be higher in the mirabegron group; however, the difference was not statistically significant. Histological examination revealed that the mirabegron group showed recovery close to normal tissue after 24h. In an acute urinary retention rat model, mirabegron maintained and restored higher bladder blood flow, resulting in protective and recovery effect after acute urinary retention.

BOO induces fibrosis and EMT in urothelial cells which can be recapitulated in vitro through elevated storage and voiding pressure cycles.

To determine the unique contributions from elevated voiding and storage pressures in the development of fibrosis and the epithelial-to-mesenchymal transition (EMT) in urothelial cells, and how progressive BOO pressure cycling is an important mechanical cue leading to these pathological changes. Urothelial cells isolated from control, SHAM, 2 (acute)- or 6 (chronic)-week BOO rats treated with an inflammasome inhibitor or no drug. Total RNA was isolated and RT-PCR was conducted with custom primers for pro-fibrotic and EMT genes. In separate experiments, a rat urothelial cell line was exposed to cyclic pressure regimes characteristic of acute and chronic BOO in the presence or absence of an inflammasome inhibitor. Following exposure, RT-PCR was conducted, collagen content was determined and intracellular caspase-1 activity was measured. Urothelial cells isolated from acute and chronic BOO rat models demonstrated expression of pro-fibrotic and EMT genes. Similarly, MYP3 rat urothelial cells subjected to pressure cycling regimes that reflect intravesical pressures in the acute or chronic BOO bladder also demonstrated increased expression of pro-fibrotic and EMT genes, along with elevated soluble collagen. Treatment with inflammasome inhibitors reduced expression of pro-fibrotic genes in the rat model and pressure cycling model but had a limited effect on EMT. These results indicate that acute and chronic BOO pressure cycling are essential in the initiation and progression of fibrosis in the bladder via the NLRP3 inflammasome, but also provide new evidence that there is also an alternative NLRP3-independent pathway leading to EMT and fibrosis.

In vivo Analysis of the Resistance of the Meshes to Escherichia coli Infection.

Background: The mesh infection is mostly related to the gram-negative bacteria, such as Escherichia coli (E. coli) for emergency surgery of incarcerated hernia. However, few study investigated the effects of E. coli concentration, mesh materials and antibiotic prophylaxis on mesh infection after hernioplasty. The aim of this study was to evaluate the bacterial resistance to E. coli for three different materials of mesh, and to measure the minimum E. coli concentration for mesh infection with and without antibiotic prophylaxis in a rat model.Methods: Three types of mesh (polytetrafluoroethylene, polypropylene, and biologic meshes) were used in the repair of an acute ventral hernia rat model in the setting of different concentrations of E. coli loads and antibiotics. At the 8th day after surgery, mesh samples were sent for microbiologic and histologic analyses.Results: The positive rates of bacterial culture increased with E. coli concentration. The biologic mesh showed better bacterial resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the concentration of E. coli ranges from 106 CFU/ml to 108 CFU/ml (P = 0.002 and P = 0.029, respectively). Prophylactical ceftriaxone treatment could not decrease the colonization rate of E. coli at 106 CFU/ml or 108 CFU/ml in each group (P > 0.05). The scores of neovascularization in polypropylene mesh and biologic mesh were similar, which was higher than that of polytetrafluoroethylene mesh (P < 0.05). Compared with other meshes, biologic mesh showed better tolerance to 106 CFU/ml E. coli with respect to inflammation, depth of inflammation, neovascularization, cellular repopulation and foreign body giant cells.Conclusion: The biologic mesh had better E. coli resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the E. coli concentration is higher than 106 CFU/ml in rats. Antibiotic prophylaxis was useful when the contamination was not particularly severe.

Glucosamine promotes seizure activity via activation of the PI3K/Akt pathway in epileptic rats

ContextGlucosamine is an amino monosaccharide with a small molecular weight and has a protective effect against various neurological diseases including multiple sclerosis and encephalomyelitis. Interestingly, low-dose glucosamine has exhibited anti-epilepsy activity. Recent studies have shown that the activation of the protein kinase B (Akt) signaling pathway may promote epilepsy. Glucosamine can increase the level of Akt phosphorylation in the brain tissue, which may aggravate epilepsy. Hence, we speculate that a higher dose of glucosamine may aggravate epilepsy via AKT signaling. ObjectiveTo investigate the effect of glucosamine on the behavior and electrophysiology of epileptic rats through PI3K/Akt pathway. MethodsGlucose (2.0 g/kg) and glucosamine (0, 0.5, 1.0, and 2.0 g/kg) were added to 2 mL of drinking water, respectively. An acute seizure rat model of lithium-pilocarpine and PTZ-kindling were constructed to observe the effects of different doses of glucosamine on epileptic behavior and hippocampal electrical activity. Meanwhile, the changes in Akt were detected by western blot. ResultsEpileptic seizures were induced by a single dose of pilocarpine or PTZ and 2.0 g/kg of glucosamine significantly prolonged the duration and severity of epileptic seizures, enhanced hippocampal electrical activity energy density, and increased phosphorylated AKT levels. A glucosamine dose of 2.0 g/kg also significantly increased the total onset energy density. Furthermore, 2.0 g/kg glucosamine facilitated the development of the chronic PTZ-kindling process. ConclusionsGlucosamine may exacerbate acute and chronic epileptic seizures via activation of the PI3K/Akt pathway in rats with experimental epilepsy.

Development of Pelubiprofen Tromethamine with Improved Gastrointestinal Safety and Absorption.

Pelubiprofen (PEL), which is a commercialized non-steroidal anti-inflammatory drug (NSAID), is associated with the risk of gastrointestinal (GI) adverse events following long-term exposure and has poor water-soluble properties. Here, a new pelubiprofen tromethamine (PEL-T) with improved solubility, permeability, GI safety, and absorption, compared to PEL, has been developed. The nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) results confirmed that the PEL-T was well formed. The powder of PEL-T showed the presence of additional 6H protons at δ 3.66–3.61 in the 1H NMR spectrum, and shifted the sharp endothermic peaks at 129 °C in DSC, and the spectrum of distinct absorption peaks in FT-IR. In addition, compared with PEL, PEL-T showed a significantly improved solubility in various media and an increased permeability coefficient (Kp) in Caco-2 cells. Furthermore, compared to PEL oral administration, PEL-T was found to significantly reduce the damaged area in an acute gastric damage rat model. The pharmacokinetic study of the PEL-T powder showed higher maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from 0 h to the last time point (AUCt) than those of the PEL powder. Taken together, our data suggest that PEL-T is a recommendable candidate with enhanced gastrointestinal safety and better absorption compared with commercial PEL.

Comprehensive analysis of the long non-coding RNA expression profile and functional roles in a contrast-induced acute kidney injury rat model.

Long non-coding RNAs (lncRNAs) have been identified as a class of regulatory RNAs that participate in both physiological and pathological conditions, including acute kidney injury. However, the roles of lncRNA dysregulation in the pathogenesis of contrast-induced acute kidney injury (CI-AKI) are largely unknown. In the present study, the expression profiles of lncRNAs in kidney tissue were compared between rats with CI-AKI and controls using high-throughput RNA sequencing. In total, 910 differentially expressed (DE) lncRNAs (DElncRNAs), including 415 downregulated and 495 upregulated lncRNAs, were identified at 12 h after intra-arterial iodinated contrast medium injection (fold change ≥2; P<0.05). Eight DElncRNAs were further selected and validated using reverse transcription-quantitative polymerase chain reaction. A previous study defined microRNA (miRNA) and mRNA expression changes in the same CI-AKI model. In the present study, a lncRNA-mRNA co-expression network comprising 349 DElncRNAs and 202 DEmRNAs was constructed. The function of these DElncRNAs was mainly associated with oxidative stress and inflammation. Additionally, lncRNA-associated competing endogenous RNA (ceRNA) analysis revealed a network comprising 40 DElncRNA nodes, 5 DEmiRNA nodes and 59 DEmRNA nodes. Among which, the carnosine dipeptidase 1-specific and the transmembrane protein 184B-specific networks were likely to be associated with CI-AKI. The results of the present study revealed the expression profile and potential roles of lncRNAs in CI-AKI, and provide a framework for further mechanistic studies.

Proteome Analysis of Urinary Biomarkers in Acute Hypercoagulable State Rat Model.

Thrombotic diseases are usually preceded by a hypercoagulable state in the body. This study aimed to screen potential urinary biomarkers for hypercoagulable state based on proteome analysis. Wistar rats were administered with the hemostatic agent etamsylate to establish hypercoagulable state. Urine samples were collected for proteome analysis. We found 20 proteins with levels more than 1.5-fold in difference between control rats and model rats. We searched human homologs of 20 rat proteins and identified 13 human proteins. Of the 13 human homologous proteins, nine were members of human core urinary proteome. Human homologous proteins of differential proteins were highly expressed in 31 human tissues, especially in the kidneys followed by digestive system and reproductive system. Surprisingly, we did not identify known coagulation factors as differential proteins in the urine of model rats. Hypercoagulable state of the body may not involve direct changes in coagulation factors but causes the changes upstream of the coagulation cascade system. Common differential urinary proteins between different hypercoagulable states suggest some common pathways in the formation of hypercoagulable states and may serve as potential biomarkers for the prevention and treatment of thrombotic diseases.

Nano dot blot: An alternative technique for protein identification and quantification in a high throughput format

BackgroundDot blot technique has been used in a similar way to western blotting, with the major difference being the lack of protein separation with electrophoresis. Protein samples are spotted over a membrane paper, the identification and quantification of a protein is achieved by immunodetection procedures such as colorimetry, fluorescence or chemiluminescence. This technique is widely accepted, but it uses large amounts of sample and antibodies to reveal the presence of the target protein. Significant milestones have been reached to achieve better results with the use of less sample and reagents; however, the ninety-six-well format is still in use. New methodIn this work, we propose an innovation to this technique, reducing the amount of sample and antibodies to identify a specific protein when compared to the regular dot blot method. Procedure consists of using a sample volume of approximately 200 nanoliters deposited with a multineedle device developed by our group. ResultsFive samples of standard protein or antigen can be spotted in a Cartesian format to identify and quantify the protein involved in physiological or pathological conditions. In addition, at least five replicates of sample or antigen are used to enable better statistics to calculate the concentration of every standard and the protein present in a sample. ConclusionsHundreds of samples can be deposited in a few minutes and analyzed in a single experimental session. To validate this method, which we called nano dot blot, six proteins involved in the inflammation process were tested in acute and chronic rat models of seizures.

Development of 20 cm sample bore size dynamic nuclear polarization (DNP)-MRI at 16 mT and redox metabolic imaging of acute hepatitis rat model

Tissue redox metabolism is involved in various diseases, and an understanding of the spatio-temporal dynamics of tissue redox metabolism could be useful for diagnosis of progression and treatment. In in vivo dynamic nuclear polarization (DNP)-MRI, electron paramagnetic resonance (EPR) irradiation at the resonance frequency of nitroxyl radicals administered as a redox probe for induction of DNP, increases the intensity of MRI signals. For electron spin, it is necessary to apply a resonant frequency 658 times higher than that required for nuclear spin because of the higher magnetic moment of unpaired electrons. Previous studies using a disease model of small animals and in vivo DNP-MRI have revealed that an abnormal redox status is involved in many diseases, and that it could be used to visualize the dynamics of alterations in redox metabolism. To use the current methods in clinical practice, the development of a prototype DNP-MRI system for preclinical examinations of large animals is indispensable for clarifying the problems peculiar to the increase in size of the DNP-MRI device. Therefore, we developed a in vivo DNP-MRI system with a sample bore size of 20 cm and a 16-mT magnetic field using a U-shaped permanent magnet. Because the NMR frequency is very low, we adopted a digital radiofrequency transmission/reception system with excellent filter and dynamic range characteristics and equipped with a digital eddy current compensation system to suppress large eddy currents. The pulse sequence was based on the fast spin-echo sequence, which was improved for low frequency and large-eddy current equipment. The in vivo DNP-MRI system developed was used to non-invasively image the redox reaction of a carbamoyl-PROXYL probe in the livers of large rats weighing 800 g. Furthermore, DNP-MRI analysis was able to capture significant changes in redox metabolism in hepatitis-model rats.

Effects of different concentrations of mesenchymal stem cells treatment on LPS-induced acute respiratory distress syndrome rat model

Purpose This study was prospectively designed to investigate the effects of different concentrations of mesenchymal stem cells treatment on respiratory mechanics, oxygenation, hemodynamics and inflammatory response in LPS-induced acute respiratory distress syndrome (ARDS) rat model. Methods: One hundred and twenty six LPS-induced ARDS model rats (weighted 200-220 g) were randomly divided into three groups: 1) Control group (N = 42); 2) low-dose hUC-MSC treatment group (MSC group 1, 1x107 cell/kg, N = 42); 3) high-dose hUC-MSC treatment group (MSC group 2, 2x107 cell/kg, N = 42), sham operation group as healthy group (N = 15). The rats were observed closely for 24 hours after hUC-MSC treatment, and the survival rate was calculated. At 24 hours, all rats were tested for hemodynamics, blood gas analysis, heart, lung, liver and kidney functions, inflammatory factors detection in blood samples and broncho-alveolar lavage fluid (BALF). The lung tissue of the rats was collected for HE staining analysis. Results: After LPS injection, ARDS was obvious in all LPS-infused rat groups, consistent with severe acute lung injury and high death rate. However, compared with the control group, a single intravenous injection hUC-MSC at dose of 1 × 107 cells/kg (low dose group) and 2 × 107 cells/kg (high dose group) reduced the mortality of rats with LPS-induced ARDS, as well as improving the lung function, increased the arterial oxygen pressure, improved the heart function, and reduced the levels of inflammatory factors including IL-1β, IL-6, and TNF-α. In addition, the high dose MSC group showed better lung injury therapeutic effects than the low dose MSC group. Data from this study demonstrated that injection of hUC-MSC had a significant therapeutic effect in treating the rat model of LPS-induced ARDS and multiple organ function injury.

Topical application of HA-g-TEMPO accelerates the acute wound healing via reducing reactive oxygen species (ROS) and promoting angiogenesis

During the occurring of cutaneous trauma, increasing oxidative stress response in wound site retards the progress of proliferation phase, impeding sequent efficient wound repair. At the same time, high-quality healing also requires adequate new blood vessels in order to furnish the wound site with a nutrient and oxygen-sufficient environment. Here we synthesized a novel hyaluronic acid (HA) material modified with a peroxidation inhibitor 2,2,6,6-tetramethylpiperidinyloxy (ATEMPO) for prevention of excessive reactive oxygen species (ROS) and promotion of angiogenesis after full-thickness skin excision in rats. Amines in ATEMPO attaching with carbonyls in HA chains was fabricated through N-acylation. The HA-g-TEMPO exerted a ROS-scavenging and angiogenesis-promoting function in vitro. In acute wound rat model, the wound closure efficacy was significantly improved to almost 55% at day 6 in comparison to 49% of HA, and wound sites in initial wound phase was also narrowed down sharply. Moreover, initially formed blood vessels were found in wound sites, further proved the angiogenesis-promoting function of HA-g-TEMPO. More interestingly, wound sites demonstrated an exciting regenerative healing effect which was characterized by marked skin appendages as well as reduced scarring. Therefore, this strategy showed a promising future that could be considered as a reliable and effective method to cutaneous wound healing.

Effect of electroacupuncture pretreatment on the protein expression of c-fos in fastigial nucleus and lateral hypothalamus area in rats with acute myocardial ischemia-reperfusion injury

To observe the effect of electroacupuncture (EA) pretreatment on the protein expression of c-fos in fastigial nucleus (FN) and lateral hypothalamus area (LHA) in rats with acute myocardial ischemia-reperfusion injury (MIRI), and to explore the role and mechanism of FN and LHA in EA at the Heart Meridian fighting against acute MIRI reaction. Seventy Sprague-Dawley rats were randomly divided into a sham operation group, a model group, an EA-Heart Meridian group and an EA-Lung Meridian group, with 14 rats in each group; an LHA lesion plus EA-Heart Meridian group (LHA+EA-Heart Meridian group) and a FN lesion plus EA-Heart Meridian group (FN+EA-Heart Meridian group), with 7 rats in each group. Except the sham operation group, the left anterior descending branch of coronary artery was ligated to establish acute MIRI rat models in the other 5 groups. In the three groups with EA-Heart Meridian treatment, Shenmen (HT 7) and Tongli (HT 5) were selected; Taiyuan (LU 9) and Lieque (LU 7) were selected in the EA-Lung Meridian group. All the EA groups received EA stimulation prior to modeling, with 1 mA in current intensity and 2 Hz in frequency, 20 min each time, once a day for a total of 7 d. The sham operation group and the model group did not receive EA stimulation. The electrocardiogram was observed in the rats to analyze the ST-segment deviation and cardiac arrhythmia score. The expression of c-fos protein in FN and LHA was detected by immunohistochemistry method. Compared with the sham operation group, the ST-segment deviation, cardiac arrhythmia score and the expression of c-fos protein in the FN and LHA increased significantly in the model group (all P<0.05). Compared with the model group, the ST-segment deviation, cardiac arrhythmia score and the expression of c-fos protein in FN and LHA decreased significantly in the EA-Heart Meridian group (all P<0.05). Compared with the EA-Heart Meridian group, the ST-segment deviation and cardiac arrhythmia score increased significantly in the EA-Lung Meridian group, LHA+EA-Heart Meridian group and FN+EA-Heart Meridian group (all P<0.05); the expression of c-fos in FN increased significantly in the EA-Lung Meridian group and LHA+EA-Heart Meridian group (both P<0.05); the expression of c-fos in LHA increased significantly in the EA-Lung Meridian group and FN+EA-Heart Meridian group (both P<0.05). FN and LHA are involved in the mechanism of EA at Heart Meridian to improve the acute MIRI reactions, and the cerebellum may participate in the improvement of cardiac function by EA through the cerebellum-hypothalamus projection.

Acute myocardial infarction therapy: in vitro and in vivo evaluation of atrial natriuretic peptide and triphenylphosphonium dual ligands modified, baicalin-loaded nanoparticulate system

Background Myocardial infarction (MI) is one of the most common ischemic heart diseases. It is very essential to explore new types of cardioprotective drugs delivery systems in this area. Objective The aim of the present study was to investigate the protective effect of baicalin (BA) and puerarin (PU) against acute MI rat models. BA and PU co-loaded nanoparticulate system were developed to improve bioavailability of the drugs, to prolong retention time in vivo and to enhance the protective effect. Methods In the present study, ANP and TPP contained ligands were synthesized. ANP/TPP-BN-LPNs were prepared and its physico-chemical properties were evaluated. The MI therapy efficiency of ANP/TPP-BN-LPNs was assessed in rats after intravenous injection. Single ligand contained LPNs, no ligand contained LPNs, and BN solution formulations were also prepared and used for the comparison. Results ANP/TPP-BN-LPNs were uniform and spheroidal particles. The size of ANP/TPP-BN-LPNs was 98.5 ± 2.9 nm, with a zeta potential of –19.5 ± 1.9 mV. The dual ligands modified LPNs exhibited significantly improved therapeutic efficiency compared with the single ligand modified LPNs and other systems. In vivo infarct therapy studies in rats proved that ANP/TPP-BN-LPNs were a promising system for efficient delivery of cardiovascular drugs for the treatment of cardiovascular diseases. Conclusions ANP/TPP-BN-LPNs could be used as a long-circulating and heart-targeting drug delivery system.

Comprehensive Analysis of Serum Metabolites Profiles in Acute Radiation Enteritis Rats by Untargeted Metabolomics

Acute radiation enteritis is a common complication occurring in patients with pelvic and abdominal tumors who receive radiotherapy. Acute radiation enteritis seriously reduces the life quality, even threatens the lives of patients. Untargeted metabolomics is an emerging strategy to explore the novel biomarkers and uncover potential pathogenesis of acute radiation enteritis. Acute radiation enteritis rat model was established by single abdominal irradiation with a gamma-ray dose of 10 Gy. Serum from 15 acute radiation enteritis rats and 10 controls was extracted for metabolomics analysis by UHPLC-Q-TOF/MS. Clinical manifestations and morphological alterations of intestine confirmed the successful establishment of acute radiation enteritis. According to the metabolomics data, 6,044 positive peaks and 4,241 negative peaks were extracted from each specimen. OPLS-DA analysis and the heat map for cluster analysis showed satisfactory discriminatory power between acute radiation enteritis rats and controls. Subsequent analysis extracted 66 significantly differentially expressed metabolites, which might be potential biomarkers for acute radiation enteritis diagnosis. Moreover, Kyoto Encyclopedia of Genes and Genomes enrichment analyses uncovered the potential mechanisms through which differentially expressed metabolites participated in acute radiation enteritis pathogenesis. To sum up, we summarized several differentially expressed serum metabolites as potential biomarkers for diagnosis of acute radiation enteritis and provide latent clues for elucidating acute radiation enteritis pathology.

Effects of water extract of Paeoniae Radix Alba on a thioacetamide induced acute liver injury rat model

Effects of water extract of Paeoniae Radix Alba on a thioacetamide induced acute liver injury rat model

Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction.

In spite of early interventions to treat acute myocardial infarction (MI), the occurrence of adverse cardiac remodeling following heart failure due to acute MI remains a clinical challenge. Thus, there is an increasing demand for the development of novel therapeutic agents capable of inhibiting the development of pathological ventricular remodeling. RNA-seq data analysis of acute MI rat models from GEO revealed that Runx1 was the most differentially expressed MI-related gene. In this study, we demonstrated that increased Runx1 expression under pathological conditions results in decreased cardiac contractile function. We identified dihydrolycorine, an alkaloid lycorine, as a promising inhibitor of Runx1. Our results showed that treatment with this drug could prevent adverse cardiac remodeling, as indicated by the downregulation of fibrotic genes using western blotting (collagen I, TGFβ, and p-smad3), downregulation of the apoptosis gene Bax, upregulation of the apoptosis gene Bcl-2, and improved cardiac functions, such as LVEF, LVSF, LVESD, and LVEDD. Additionally, dihydrolycorine treatment could rescue cardiomyocyte hypertrophy as demonstrated by wheat germ agglutinin staining, increased expression levels of the punctuate gap junction protein connexin 43, and decreased α-SMA expression, resulting in cardiomyocyte fibrosis in immunofluorescence staining. Molecular docking, binding modeling, and pull-down assays were used to identify potential dihydrolycorine-binding sites in Runx1. When Ad-sh-Runx1 was transfected into hypoxia-cardiomyocytes or injected into the hearts of MI rats, the cardioprotective effects of dihydrolycorine were abolished, and the normal electrophysiological activity of cardiomyocytes was disrupted. Taken together, the results of the present study indicate that dihydrolycorine may inhibit adverse cardiac remodeling after MI through the reduction of Runx1, suggesting that dihydrolycorine-mediated-Runx1 regulation might represent a novel therapeutic approach for adverse cardiac remodeling after MI.

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model.

Mounting evidence indicates that the mesenchymal stem cell (MSC) injection is safe and efficacious for treating cardiomyopathy; however, there is limited information relating to multiple intravenous injections of human-induced pluripotent stem cell-derived mesenchymal stem cell (hiPSC-MSC) and long-term evaluation of the cardiac function. In the current study, MSC-like cells were derived from human-induced pluripotent stem cells through valproic acid (VPA) induction and continuous cell passages. The derived spindle-like cells expressed MSC-related markers, secreted angiogenic and immune-regulatory factors, and could be induced to experience chondrogenic and adipogenic differentiation. During the induction process, expression of epithelial-to-mesenchymal transition- (EMT-) related gene N-cadherin and vimentin was upregulated to a very high level, and the expression of pluripotency-related genes Sox2 and Oct4 was downregulated or remained unchanged, indicating that VPA initiated EMT by upregulating the expression of EMT promoting genes and downregulating that of pluripotency-related genes. Two and four intravenous hiPSC-MSC injections (106 cells/per injections) were provided, respectively, to model rats one week after acute myocardial infarction (AMI). Cardiac function parameters were dynamically monitored during a 12-week period. Two and four cell injections significantly the improved left ventricular ejection fraction and left ventricular fractional shortening; four-injection markedly stimulated angiogenesis reduced the scar size and cell apoptosis number in the scar area in comparison with that of the untreated control model rats. Although the difference was insignificant, the hiPSC-MSC administration delayed the increase of left ventricular end-diastolic dimension to different extents compared with that of the PBS-injection control. No perceptible immune reaction symptom or hiPSC-MSC-induced tumour formation was found over 12 weeks. Compared with the PBS-injection control, four injections produced better outcome than two injections; as a result, at least four rounds of MSC injections were suggested for AMI treatment.