Showing papers on "Intraperitoneal injection published in 2013"
TL;DR: It is suggested that ferulic acid acts as a protective agent in diabetic rats by altering oxidative stress, expression of pro-inflammatory cytokines and apoptosis.
Abstract: In the present study, we aimed to investigate the protective effect of ferulic acid at different doses (50 mg/kg alternative day and 50 mg/kg daily) on diabetic rats and to explore the interrelationship between oxidative stress and cytokines correlates with apoptotic events in pancreatic tissue. Male Wistar rats were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). Ferulic acid was administered orally for 8 weeks. At the end of the study, all animals were sacrificed. Blood samples were collected for the biochemical estimations and pancreas was isolated for antioxidant status, histopathological, immunohistochemical, and apoptotic studies. Treatment with ferulic acid to diabetic rats significantly improved blood glucose, serum total cholesterol, triglycerides, creatinine, urea, and albumin levels toward normal. Furthermore, decrement of the elevated lipid peroxidation levels and increment of the reduced superoxide dismutase, catalase, and reduced glutathione enzyme activities in pancreatic tissues were observed in ferulic acid-treated groups. Ferulic acid-treated rats in the diabetic group showed an improved histological appearance. Our data also revealed a significant reduction in the activity of apoptosis using terminal dUTP nick end-labeling and reduced expression of TGF-β1 and IL-1β in the pancreatic β-cell of ferulic acid-treated rats. Treatment with ferulic acid daily doses produced a significant result compared to alternative dose. Collectively our results suggested that ferulic acid acts as a protective agent in diabetic rats by altering oxidative stress, expression of pro-inflammatory cytokines and apoptosis.
113 citations
TL;DR: Results demonstrate that Cur attenuated testicular damage in diabetic rats by decreasing oxidative stress.
Abstract: Scope
The present study was designed to examine the protective and antioxidative effects of curcumin (Cur) on streptozotocin (STZ) induced testicular damage, apoptotic germ cell death, and oxidative stress.
Methods and results
Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). The rats in the Cur-treated group were given Cur (100 mg/kg) once a day intragastrik for 8 weeks starting 3 days prior to STZ injection. Cur treatment significantly decreased the elevated tissue malondialdehyde levels and increased the reduced superoxide dismutase, and glutathione peroxidase enzyme activities in testis tissues samples. The Cur-treated rats in the diabetic group showed an improved histological appearance and serum testosterone levels. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling and there was a rise in the expression of proliferating cell nuclear antigen in testis tissues of Cur-treated rats in the diabetic group.
Conclusion
These results demonstrate that Cur attenuated testicular damage in diabetic rats by decreasing oxidative stress.
97 citations
Journal Article•
TL;DR: Compared with KX, intraperitoneal administration of KD offered better local tolerance and anesthesia of similar quality and depth, and was associated with mild transient increases in serum ALT and AST concentrations in the absence of histomorphologic findings in liver.
Abstract: We compared ketamine–xylazine (K, 100 mg/kg; X, 10 mg/kg) and ketamine–dexmedetomidine (K, 75 mg/kg; D, 10 mg/kg) for their ability to produce anesthesia, their tissue tolerance, and the reversibility of their effects by atipamezole (10 mg/kg) after intraperitoneal administration to Wistar Han rats Both anesthetic combinations led to a comparable level of anesthesia over a 30-min period However, the administration of KD led to a 20% decrease in heart rate, 33% decrease in respiratory rate, and a 20% decrease in peripheral oxygen saturation from baseline levels Intraperitoneal administration of saline and both anesthetic combinations was associated with mild transient increases in serum ALT and AST concentrations in the absence of histomorphologic findings in liver Muscle and tissue necrosis at the intraperitoneal injection sites correlated with increases in serum creatine kinase concentrations in rats given KD or KX; these increases were more severe in the KX group than the KD group Compared with KX, intraperitoneal administration of KD offered better local tolerance and anesthesia of similar quality and depth
90 citations
TL;DR: The results show that intraperitoneal injection of clodronate liposomes effectively depleted VATMs, which blocked high-fat diet-induced weight gain, fat accumulation, insulin resistance, and hepatic steatosis and suggest that adipose tissue macrophages could be regarded as a potential target for drug development in prevention and therapy of obesity and obesity-associated complications.
Abstract: Macrophage infiltration in adipose tissue is strongly correlated with obesity. The exact role of macrophage in the development of obesity, however, has not been fully understood. In this study, using intraperitoneal injection of clodronate liposomes, we tissue-specifically depleted visceral adipose tissue macrophages (VATMs) and explored their roles in initiation and progression of obesity. Two sets of experiments were conducted, using mice on a high-fat diet as the animal model. Mice were injected with clodronate liposomes at the beginning of high-fat diet feeding to investigate the role of VATMs in the initiation of obesity. Treatment starting on week 5 was designed to explore the function of VATMs in the progression of weight gain. The results show that intraperitoneal injection of clodronate liposomes effectively depleted VATMs, which blocked high-fat diet-induced weight gain, fat accumulation, insulin resistance, and hepatic steatosis. Similarly, clodronate liposomes suppressed progression of weight gain in mice after being fed with a high-fat diet for 4 weeks and improved insulin sensitivity. Gene expression analysis showed that depletion of VATMs was associated with downregulation of the expression of genes involved in lipogenesis and gluconeogenesis including acc1, fas, scd1, and pepck, decreased expression of genes involved in chronic inflammation including mcp1 and tnfα, and suppressed expression of macrophage specific marker genes of f4/80 and cd11c in adipose tissue. Depletion of VATMs was associated with prevention of the formation of crown-like structures in white adipose tissue and the maintenance of a low level of blood TNF-α. Collectively, these data demonstrate that VATMs appeared to play a crucial role in the development of obesity and obesity-associated diseases and suggest that adipose tissue macrophages could be regarded as a potential target for drug development in prevention and therapy of obesity and obesity-associated complications.
79 citations
TL;DR: Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers, smooth muscle markers, and pericyte markers in cavernoursal tissue.
Abstract: The aim of this study was to determine whether adipose derived stem cells (ADSCs) expressing vascular endothelial growth factor (VEGF) gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED) model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg), and then screened by apomorphine (100 µg/kg). Five groups were used (n = 12/group)–Group 1 (G1): intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1–G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p<0.01) than those with ADSCs or lentivirus-VEGF injection. Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers (VEGF, VEGF R1, VEGF R2, eNOS, CD31 and vWF), smooth muscle markers (a-actin and smoothelin), and pericyte markers (CD146 and NG2). ADSCs expressing VEGF produced a therapeutic effect and restored erectile function in diabetic rats by enhancing VEGF-stimulated endothelial function and increasing the contents of smooth muscle and pericytes.
79 citations
TL;DR: Findings suggest that β-caryophyllene has a potent neuroprotective activity, and its neuroprotection may be partly related to the modulation of inflammatory mediators.
Abstract: β-Caryophyllene (trans-4,11,11-trimethyl-8-methylenebicyclo[7,2,0]undec-4-ene), found in various plants, is a natural bicyclic sesquiterpene with a low toxicity. Here, we show that a single intraperitoneal injection of β-caryophyllene (10 mg/kg) significantly reduced the cortical infarct volume by 67% when given immediately before middle cerebral artery occlusion (MCAO). Neurological deficits caused by MCAO were also significantly decreased by β-caryophyllene. β-Caryophyllene treatment of cortical cells exposed to oxygen–glucose deprivation revealed a significant protection in a dose-dependent manner. However, β-caryophyllene neither suppressed N-methyl-d-aspartate excitotoxicity in cultured cortical cells nor markedly decreased the oxidative stress measured in the cellular or acellular systems. By contrast, treatments with β-caryophyllene dose-dependently inhibited mRNA expression of inducible nitric oxide synthetase, interleukin (IL)-1β, IL-6, and cyclooxygenase 2 in C6 microglial cells, and de...
65 citations
TL;DR: In vivo and in vitro assays suggested that the IO-NPs could be further used for developing new in vivo medical applications and not cytotoxic on HeLa cells.
Abstract: The aim of this study was to evaluate the biological properties of iron oxide nanoparticles (IO-NPs) obtained in the aqueous suspension. The iron oxide nanoparticles were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The biocompatibility of the iron oxide was demonstrated by the in vitro quantification of HeLa cells viability using propidium iodide (PI) and fluorescein diacetate (FdA) and the MTT colorimetric assay. The toxicity of small size iron oxide nanoparticles was also evaluated by means of histological examination on male Brown Norway rats after intraperitoneal injection. At the tested concentrations, the nanoparticles proved to be not cytotoxic on HeLa cells. The rat's behavior, as well as the histopathological aspect of liver, kidney, lung, and spleen tissues at 48 h after intraperitoneal injection did not present any modifications. The in vivo and in vitro assays suggested that the IO-NPs could be further used for developing new in vivo medical applications.
65 citations
TL;DR: Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.
Abstract: Objectives: The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated.
Methods: Acute pancreatitis was induced in C57BL mice by intraperitoneal injection of 50 μg/kg cerulein hourly, with a total of 6 times. Drugs (O-1602, 10 mg/kg, or CBD, 0.5 mg/kg) were given by intraperitoneal injection 2 times at 30 minutes before the first injection and immediately before the fifth cerulein injection. At 3 hours after the last injection, the blood, the lungs, and the pancreas were harvested for the pancreatic enzyme activity, myeloperoxidase activity, and pro-inflammatory cytokines measurement; and the expressions of GPR55 mRNA and protein in the pancreas were detected.
Results: Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor α; levels, and the myeloperoxidase activities in plasma and in the organ tissues. G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent.
Conclusion: Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.
64 citations
TL;DR: In this paper, the authors examined the effect of n-3 fatty acid carried in N-3 rich triglyceride (TG) emulsions in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury.
Abstract: We questioned if acute administration of n-3 fatty acids (FA) carried in n-3 rich triglyceride (TG) emulsions provides neuroprotection in neonatal mice subjected to hypoxic-ischemic (H/I) brain injury. We examined specificity of FA, optimal doses, and therapeutic windows for neuroprotection after H/I. H/I insult was induced in C57BL/6J 10-day-old mice by right carotid artery ligation followed by exposure to 8% O2 for 15 minutes at 37°C. Intraperitoneal injection with n-3-rich TG emulsions, n-6 rich TG emulsions or saline for control was administered at different time points before and/or after H/I. In separate experiments, dose responses were determined with TG containing only docosahexaenoic acid (Tri-DHA) or eicosapentaenoic acid (Tri-EPA) with a range of 0.1–0.375 g n-3 TG/kg, administered immediately after H/I insult. Infarct volume and cerebral blood flow (CBF) were measured. Treatment with n-3 TG emulsions both before- and after- H/I significantly reduced total infarct volume by a mean of 43% when administered 90 min prior to H/I and by 47% when administered immediately after H/I. In post-H/I experiments Tri-DHA, but not Tri-EPA exhibited neuroprotective effects with both low and high doses (p<0.05). Moreover, delayed post-H/I treatment with Tri-DHA significantly decreased total infarct volume by a mean of 51% when administered at 0 hr, by 46% at 1 hr, and by 51% at 2 hr after H/I insult. No protective effect occurred with Tri-DHA injection at 4 hr after H/I. There were no n-3 TG related differences in CBF. A significant reduction in brain tissue death was maintained after Tri-DHA injection at 8 wk after the initial brain injury. Thus, n-3 TG, specifically containing DHA, is protective against H/I induced brain infarction when administered up to 2 hr after H/I injury. Acute administration of TG-rich DHA may prove effective for treatment of stroke in humans.
59 citations
TL;DR: Results indicate that AG is an efficient cytoprotective agent against Hg-induced nephrotoxicity by a mechanism related at least in part to its ability to decrease oxidative and nitrosative stress and preserve the activity of antioxidant enzymes in kidney tissues.
Abstract: The effects of Arabic gum (AG) against nephrotoxicity of mercury (Hg), an oxidative-stress inducing substance, in rats were investigated. A single dose of mercuric chloride (5 mg/kg intraperitoneal injection) induced renal toxicity, manifested biochemically by a significant increase in serum creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite production in kidney tissues. In addition, reduced glutathione, glutathione peroxidase, and catalase enzymes in renal tissues were significantly decreased. Pretreatment of rats with AG (7.5 g/kg/day per oral administration), starting 5 days before mercuric chloride injection and continuing through the experimental period, resulted in a complete reversal of Hg-induced increase in creatinine, blood urea nitrogen, thiobarbituric acid reactive substances, and total nitrate/nitrite to control values. Histopathologic examination of kidney tissues confirmed the biochemical data; pretreatment of AG prevented Hg-induced degenerative changes of kidney tissues. These results indicate that AG is an efficient cytoprotective agent against Hg-induced nephrotoxicity by a mechanism related at least in part to its ability to decrease oxidative and nitrosative stress and preserve the activity of antioxidant enzymes in kidney tissues.
57 citations
TL;DR: Single α-MSH(11–13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury.
Abstract: Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of α-MSH, the C-terminal tripeptide α-MSH(11–13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels increased over time with a 3-fold maximum at 12 h compared to naive brain tissue. The effect of α-MSH(11–13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg α-MSH(11–13) or 0.9% NaCl) showed a considerable smaller trauma in α-MSH(11–13) injected mice. The expression of the inflammatory markers TNF-α and IL-1β as well as the total amount of Iba-1 positive cells were not reduced. However, cell branch counting of Iba-1 positive cells revealed a reduced activation of microglia. Furthermore, tripeptide injection reduced neuronal apoptosis analyzed by cleaved caspase-3 and NeuN staining. Based on the results single α-MSH(11–13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury.
TL;DR: It is indicated that repeated intravenous ASC can reduce diabetic kidney damage in rats even at the progressive stage, and promote podocyte recovery via GDNF secretion.
Abstract: Adipose-derived stem cells (ASCs) can alleviate acute kidney injury and promote kidney cell regeneration and repair. To investigate the role of ASCs in diabetic nephropathy (DN), Sprague-Dawley rats were made diabetic by intraperitoneal injection of streptozotocin (STZ) after uninephrectomy. After 12 weeks, proteinuria was well established. Five times of 5×106 human ASCs repeatedly injected through a tail vein at 4 weekly intervals. A reduction in proteinuria was not observed in diabetic rats until 24 weeks. However, urinary protein excretion was significantly suppressed at 28 weeks and persisted up to 32 weeks after STZ treatment. ASC treatment significantly attenuated glomerulus hypertrophy and tubular interstitial injury, and led to the downregulation of WT-1 and synaptopodin expression. CFSE labeled ASCs were injected into DN rats via the tail vein. Within 24 h after injection, the cells were detected in lung, spleen, and peritubular regions, but rarely in pancreas. Human Alu gene expression was detec...
TL;DR: The result shows that phoenixin is expressed in sensory neurons of the dorsal root, nodose and trigeminal ganglia, the amidated peptide is bioactive, and exogenously administered phPhoenixin may preferentially suppress visceral as opposed to thermal pain.
TL;DR: The results showed that the blood glucose levels in the diabetic mice were significantly reduced by PCE-C from 15.32 ± 4.38 mM to 5.77 ±-1.46 m mM.
TL;DR: In insight into the observed toxicological effect levels and tissue‐specific distribution of CdSe/CdS‐MPA QDs, the levels of interleukin‐6, a pro‐inflammatory marker, were increased in the plasma, liver and spleen.
Abstract: Quantum dots (QDs) are novel tools with multiple biological and medical applications because of their superior photoemission and photostability characteristics. However, leaching of toxic metals from QDs is of great concern. Therefore, for the successful application of QDs in bioscience, it is essential to understand their biological fate and toxicity. We investigated toxicological effects and tissue distribution of mercaptopropionic acid-conjugated cadmium selenide/cadmium sulfide (CdSe/CdS-MPA) QDs after repeated intraperitoneal injection into BALB/c mice. The mice were injected every 3 days with various doses of QDs (0, 5, 10 and 25 mg kg−1). The subsequent effects of QDs on plasma levels of various biomarkers were evaluated at different time points (at 0, 1, 4, 7, 10, 13 and 15 days). Various tissue samples (spleen, liver, lung, kidneys, brain, heart and thymus) were collected for toxicity analysis, distribution testing, histopathological examination and inflammation assessment. No abnormal clinical signs or behaviors were recorded but the body weight of mice treated with 25 mg kg−1 QDs was significantly decreased from day 7 compared with control mice. QDs were observed in the liver, spleen, lung and kidneys, but not in brain or heart. Significantly higher levels of lactate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase were found in the plasma, liver and spleen. Histopathological examination did not show any tissue toxicity but the levels of interleukin-6, a pro-inflammatory marker, were increased in the plasma, liver and spleen. All of these findings provide insight into the observed toxicological effect levels and tissue-specific distribution of CdSe/CdS-MPA QDs. Copyright © 2012 John Wiley & Sons, Ltd.
TL;DR: Injection of rHuEPO enhance recovery from CP-induced AKI in rats by ameliorating renal functional impairment and exerting important anti-apoptotic effects and a possible mechanism involving PI3K/Akt activation and the inhibition of ER stress-mediated apoptosis is investigated.
Abstract: Background The anticancer drug cisplatin (CP)-induced nephrotoxicity associated with apoptosis plays crucial roles in tumor patients. Erythropoietin (EPO) has recently been shown to enhance recovery from CP-induced acute kidney injury (AKI) in rats by exerting anti-apoptotic effects. However, the molecular mechanisms of Erythropoietin protects against CP-induced AKI are not very clear. The present study investigated the protective effects of erythropoietin (EPO) against CP-induced nephrotoxicity and the possible mechanism in rats. Methods Sprague-Dawley (SD) rats were randomly divided into four groups: (1) Control group (n=16): which received a single intraperitoneal injection of vehicle (0.9% saline; 5 mL/kg); (2) CP group (n=16): which received a single intraperitoneal injection of 10.0 mg/kg CP (previously dissolved at 2.0 mg/mL in 0.9% saline solution); (3) CP+rHuEPO group (n=16): which received rHuEPO (5000 U/kg) with co-injection of the LY294002 vehicle dimethyl sulfoxide (DMSO, 33.3 µL/kg; Sigma, St. Louis, MO, USA) by tail vein injection 2 days before CP administration, 15 min before CP administration, and 2 days after CP administration; (4) CP+rHuEPO+LY group (n=16): which received LY294002 (0.3 mg/kg) 10 min before rHuEPO administration by three injections into the tail vein at 2-day intervals beginning 2 days before CP administration. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. The expressions of C/EBP-homologous protein (CHOP), glucose-regulated protein 78 (GRP78), caspase-12, the phosphorylation of Akt, cleaved-caspase-3 and EPO receptor (EPOR) were measured after CP-treated. In addition, light microscopy and immunohistochemistry examinations were performed. Results The levels of serum urea and creatinine were increased at 96 h after CP-administered group. The eHuEPO-administered group had significantly lower serum creatinine levels. CP caused an increase in TUNEL-positive cells that was accompanied and apoptotic cell death induced by CP was significantly abrogated by rHuEPO at 96h by morphological evidence of apoptosis. The over-expression of CP-induced endoplasmic reticulum (ER) stress markers (CHOP and GRP78) and activation of caspase-12 were suppressed by rHuEPO, which also attenuated the CP-induced suppression of phosphatidylinositol-3kinase/Akt (PI3K/Akt) signaling in rat kidneys. In addition, LY294002 diminished the effect of rHuEPO on renal protection and antiapoptosis. Conclusions Injection of rHuEPO enhance recovery from CP-induced AKI in rats by ameliorating renal functional impairment and exerting important anti-apoptotic effects. However, rHuEPO inhibited CP-induced AKI by a possible mechanism involving PI3K/Akt activation and the inhibition of ER stress-mediated apoptosis.
TL;DR: Investigation of the protective effect of methanolic neem leaves extract on rats treated with cisplatin (CDDP)-induced hepatotoxicity found it may have a potential role when combined with cisPlatin in chemotherapy to alleviate cis platin-induced damage and oxidative stress in liver.
Abstract: Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a) histological changes, (b) tissue biochemical oxidant and antioxidant parameters, and (c) investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver.
TL;DR: Results suggest that the naphthenic acids may act via a generally toxic mechanism rather than by specific toxic effects on immune cells, as similar dose of benzo[a]pyrene caused a significant decrease in B- and T-lymphocyte absolute counts in blood and relative B-ly mphocyte counts in spleen.
TL;DR: Despite severe damage, liver cells in the damaged area do not simply die but instead display locally adjusted gene expression supporting damage response and recovery, suggesting complementarity of variant liver functions like protein production, glucose homeostasis and detoxification.
Abstract: Zonation of metabolic activities within specific structures and cell types is a phenomenon of liver organization and ensures complementarity of variant liver functions like protein production, glucose homeostasis and detoxification. To analyze damage and regeneration of liver tissue in response to a toxic agent, expression of liver specific enzymes was analyzed by in situ hybridization in mouse over a 6 days time course following carbon tetrachloride (CCl4) injection. CCl4 mixed with mineral oil was administered to BALB/c mice by intraperitoneal injection, and mice were sacrificed at different time points post injection. Changes in the expression of albumin (Alb), arginase (Arg1), glutaminase 2 (Gls2), Glutamine synthetase (Gs), glucose-6-phosphatase (G6pc), glycogen synthase 2 (Gys2), Glycerinaldehyd-3-phosphat-Dehydrogenase (Gapdh), Cytochrom p450 2E1 (Cyp2e1) and glucagon receptor (Gcgr) genes in the liver were studied by in situ hybridization and qPCR. We observed significant changes in gene expression of enzymes involved in nitrogen and glucose metabolism and their local distribution following CCl4 injury. We also found that Cyp2e1, the primary metabolizing enzyme for CCl4, was strongly expressed in the pericentral zone during recovery. Furthermore, cells in the damaged area displayed distinct gene expression profiles during the analyzed time course and showed complete recovery with strong albumin production 6 days after CCl4 injection. Our results indicate that despite severe damage, liver cells in the damaged area do not simply die but instead display locally adjusted gene expression supporting damage response and recovery.
TL;DR: OM-174 therapy was well tolerated at biologically active concentrations and further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect.
Abstract: Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion. Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 μg/m2. Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed. Seventeen patients were included. The highest dose administered was 1000 μg/m2 repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 μg/m2 of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of TNF-alpha and IL-6 concentrations were detected after the first infusion and decreased progressively suggesting tolerance. OM-174 therapy was well tolerated at biologically active concentrations. Whereas the recommended dose was not determined, further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect. NCT01800812
(ClinicalTrials.gov Identifier).
TL;DR: These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1.
Abstract: Citrullinemia type 1 (CTLN1) is an autosomal recessive disorder of metabolism caused by a deficiency of argininosuccinate synthetase. Despite optimal management, CTLN1 patients still suffer from lethal metabolic instability and experience life-threatening episodes of acute hyperammonemia. A murine model of CTLN1 (fold/fold) that displays lethality within the first 21 days of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy. An AAV serotype 8 (AAV8) vector was engineered to express the human ASS1 cDNA under the control of a liver-specific promoter (thyroxine-binding globulin, TBG), AAV8-TBG-hASS1, and delivered to 7-10 days old mice via intraperitoneal injection. Greater than 95% of the mice were rescued from lethality and survival was extended beyond 100 days after receiving a single dose of vector. AAV8-TBG-hASS1 treatment resulted in liver-specific expression of hASS1, increased ASS1 enzyme activity, reduction in plasma ammonia and citrulline concentrations and significant phenotypic improvement of the fold/fold growth and skin phenotypes. These experiments highlight a gene transfer approach using AAV8 vector for liver-targeted gene therapy that could serve as a treatment for CTLN1.
TL;DR: Intraperitoneal injection of CSE produced emphysema, pulmonary parenchymal apoptosis, and injury of cardiac and skeletal muscles in mice, and all pathobiologically relevant mechanisms in this model are shared with the COPD patients.
Abstract: Background: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive, airway disease. In order to recognize mechanisms of COPD, various types of COPD animal models have been established, and the pathogenesis are different. The present study was designed to establish a COPD animal model by intraperitoneal injection of cigarette smoke extract (CSE) in BALB/C mice. Methods: Mice were injected intraperitoneally with PBS/CSE and sacrificed at day 28. Pulmonary function, pathology of lung tissue, morphology of hearts and skeletal muscle, leukocytes count and antioxidant activity of bronchoalveolar lavage fluid (BALF), pulmonary parenchymal apoptosis index (AI), expression of cleaved caspase-3, expression of MMP-2 and MMP-9 mRNA, and activity of MMP-2 and MMP-9 in lung tissue were measured. Results: Intraperitoneal injection of CSE induced pulmonary parenchymal destruction, pulmonary function reduction, leukocytes count, injury of cardiac and peripheral muscles, and increased pulmonary pare...
TL;DR: Data indicate for the first time that 13-desMeC cross the blood brain barrier and shows in vivo beneficial effects against AD after administration of low intraperitoneal doses of this marine toxin.
Abstract: Spirolides are marine toxins that are not currently in the routine monitoring assays. Nicotinic receptors seem to be the target of these compounds making them a promising pharmacological tool for related diseases as dementias as previously shown in vitro. In the present work, the bioavailability of 13-desMethyl spirolide C (13-desMeC) in the brain and in vivo effects were tested. Bioavailability was studied by ultra-performance liquid chromatography-mass spectrometry and its effect over Alzheimer hallmarks was studied by Proton magnetic resonance spectroscopy (H-MRS) and western blot. Only 2 minutes after its intraperitoneal injection it is found in brain and remains detectable even 24 hours post administration. Based on previous works that showed beneficial effects in an in vitro model of Alzheimer´s disease (AD), we studied the effect in the same mice, 3xTg-AD, in vivo. We found that 13-desMeC (11.9 ug/kg, i.p.) induced positive effects on AD markers with an increase in N-acetyl aspartate (NAA) levels. These results were supported by an increase in synaptophysin levels and also a decrease in the intracellular amyloid beta levels in the hippocampus of treated 3xTg- AD versus non treated mice remarking the positive effects of this molecule in a well known model of AD. These data indicate for the first time that 13-desMeC cross the blood brain barrier and shows in vivo beneficial effects against AD after administration of low intraperitoneal doses of this marine toxin. This toxin may inspire a novel medical treatment of age-related diseases.
TL;DR: The cardioprotective effects of necroStatin-1 and necrostatin-5 were studied on the isolated heart model in rats and produced a positive inotropic effect, but did not reduce the infarction zone.
Abstract: The cardioprotective effects of necroptosis inhibitors necrostatin-1 and necrostatin-5 were studied on the isolated heart model in rats. Intraperitoneal injection of necrostatin-1 (1.65 mg/kg) or necrostatin-5 (2.46 mg/kg) 60 min before reperfusion of the isolated heart reduced the infarction zone caused by 30-min global ischemia and 120-min reperfusion. Intracoronary injection of necrostatin-1 (44.5 μmol/liter) caused an increase of left-ventricular systolic pressure, that is produced a positive inotropic effect, but did not reduce the infarction zone.
TL;DR: Overall, the data show an equal inflammatory response to burn injury when intoxication is achieved by either i.p. injection or oral gavage, suggesting that findings from studies using either ethanol paradigm are directly comparable.
Abstract: The increasing prevalence of binge drinking and its association with trauma necessitate accurate animal models to examine the impact of intoxication on the response and outcome to injuries such as burn. While much research has focused on the effect of alcohol dose and duration on the subsequent inflammatory parameters following burn, little evidence exists on the effect of the route of alcohol administration. We examined the degree to which intoxication before burn injury causes systemic inflammation when ethanol is given by intraperitoneal (i.p.) injection or oral gavage. We found that intoxication potentiates postburn damage in the ileum, liver, and lungs of mice to an equivalent extent when either ethanol administration route is used. We also found a similar hematologic response and levels of circulating interleukin-6 (IL-6) when either ethanol paradigm achieved intoxication before burn. Furthermore, both i.p. and gavage resulted in similar blood alcohol concentrations at all time points tested. Overall, our data show an equal inflammatory response to burn injury when intoxication is achieved by either i.p. injection or oral gavage, suggesting that findings from studies using either ethanol paradigm are directly comparable.
TL;DR: Treatment of chronic iron-overloaded mice with SM dose-dependently ameliorated changes in hepatic morphology and coefficient, and displayed anti-fibrotic activity in the liver induced by chronic iron overload, which may be attributed to multitargeted inhibition of iron deposition and collagen accumulation, as well as oxidative stress, inflammation and apoptosis.
TL;DR: The data suggest that intraperitoneal injection of IL-4 or IL-10 plasmid was a potential strategy in control of TNBS-induced murine colitis, but their combination had less effect.
Abstract: Inflammatory bowel disease (IBD) is characterized by disturbance of pro-inflammatory cytokines and anti-inflammatory cytokines. Previous studies have demonstrated the effect of anti-inflammatory cytokines, such as interleukin-10 (IL-10) or IL-4 on IBD, but their data were controversial. This study further investigated the effect of IL-4 (IL-4), IL-10 and their combination on treatment of trinitrobenzenesulfonic acid (TNBS)-induced murine colitis. pcDNA3.0 carrying murine IL-4 or IL-10 cDNA was encapsulated with LipofectAMINE 2000 and intraperitoneally injected into mice with TNBS-induced colitis. The levels of intestinal IL-4 and IL-10 mRNA were confirmed by quantitative-RT-PCR. Inflamed tissues were assessed by histology and expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-6. The data confirmed that IL-4 or IL-10 over-expression was successfully induced in murine colon tissues after intraperitoneal injection. Injections of IL-4 or IL-10 significantly inhibited TNBS-induced colon tissue damage, disease activity index (DAI) and body weight loss compared to the control mice. Furthermore, expression of IFN-γ, TNF-α and IL-6 was markedly blocked by injections of IL-4 or IL-10 plasmid. However, there was less therapeutic effect in mice injected with the combination of IL-4 and IL-10. These data suggest that intraperitoneal injection of IL-4 or IL-10 plasmid was a potential strategy in control of TNBS-induced murine colitis, but their combination had less effect.
TL;DR: Intraperitoneal injection of H2 is a novel hydrogen administration method and can reduce cerebral ischemia-reperfusion injury and improve the prognosis of cardiopulmonary cerebral resuscitation in a rabbit model of CA.
TL;DR: It is concluded that EPO may play a primary role against the progression of diabetic retinopathy by reducing blood vessel degeneration at a very early disease stage.
TL;DR: Melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations, indicating that melatonin administration could be an alternative and effective treatment during chemotherapy.
Abstract: The antioxidant and free radical scavenger properties of melatonin have been well described in the literature. In this study, our objective was to determine the protective effect of the pineal gland hormone against the DNA damage induced by cyclophosphamide (CP), an anti-tumor agent that is widely applied in clinical practice. DNA damage was induced in rats by a single intraperitoneal injection of CP (20 or 50 mg/kg). Animals received melatonin during the dark period for 15 days (1 mg/kg in the drinking water). Rat bone marrow cells were used for the determination of chromosomal aberrations and of formamidopyrimidine DNA glycosylase enzyme (Fpg)-sensitive sites by the comet technique and of Xpf mRNA expression by qRT-PCR. The number (mean ± SE) of chromosomal aberrations in pinealectomized (PINX) animals treated with melatonin and CP (2.50 ± 0.50/100 cells) was lower than that obtained for PINX animals injected with CP (12 ± 1.8/100 cells), thus showing a reduction of 85.8% in the number of chromosomal aberrations. This melatonin-mediated protection was also observed when oxidative lesions were analyzed by the Fpg-sensitive assay, both 24 and 48 h after CP administration. The expression of Xpf mRNA, which is involved in the DNA nucleotide excision repair machinery, was up-regulated by melatonin. The results indicate that melatonin is able to protect bone marrow cells by completely blocking CP-induced chromosome aberrations. Therefore, melatonin administration could be an alternative and effective treatment during chemotherapy.