Single Intraperitoneal Administration Research Articles

Фармакологическая коррекция нарушений системы гемостаза, вызванных применением цисплатина

A single intraperitoneal administration of cisplatin in the MTD to outbred female mice disturbed hemostasis and formed the procoagulant phenotype of hemostatic potential on days 7-10 culminating in a pronounced hypocoagulation on day 15. Hemostasis was corrected with warfarin and an extract containing furocoumarins composed of isopimpinellin (42.97%), bergapten (35.18%), and xanthotoxin (15.41%). The extract was standardized with gas chromatography-mass spectrometry, thin-layer chromatography, and HPLC. Furocoumarins and reference drug warfarin were administered intragastrically during 4 days starting on day 6 after the administration of cisplatin. Both furocoumarins and warfarin corrected hypercoagulation on days 7-10. On day 10, furocoumarins normalized coagulation, whereas warfarin resulted in hypocoagulation. On days 15-30, no effects of warfarin were observed. furocoumarins corrected hypocoagulation on days 15-20 with prolongation of this effect up to experimental day 30.

Effect of acute insulin therapy on the concentration of vascular endothelial growth factor A (VEGF-A) in the intraocular fluid in an experiment

To study the effect of insulin therapy on the concentration of vascular endothelial growth factor A (VEGF-A) in the intraocular fluid of rats with alloxan model of diabetes mellitus. The experiment was conducted on 80 mongrel rats. In 65 rats, the alloxan model of diabetes mellitus was simulated by a single intraperitoneal injection of 100 mg/kg alloxan hydrate saluted in 0.4 ml of citrate buffer. 72 hours after intraperitoneal administration of alloxan monohydrate, these animals were divided into 2 groups. The main group (group 1) consisted of animals with alloxan model of diabetes mellitus, who started daily single intraperitoneal administration of prolonged-acting insulin at a therapeutic dose of 0.9 U/kg Body weight. The comparison group (group 2) consisted of animals with alloxan model of diabetes mellitus who did not receive specific therapy. 15 healthy rats constituted the control group (group 3). Experimental animals were removed from the study on day 31 of insulin therapy. The concentration of VEGF-A was determined in 80-90 μl of intraocular fluid collected from both eyes of each animal. In the main group, the median of VEGF-A concentration [25th; 75th percentiles] in the intraocular fluid was 140 [136; 210] pg/ml, which is 1.94 times higher than in the comparison group (72 [58; 86] pg/ml) and 1.84 times higher than in the control group (76 [62.5; 88] pg/ml). The concentration of VEGF-A in the intraocular fluid in the main group was statistically significantly higher, as compared with the comparison group (pm-u<0.0004), and compared with the control group (pm-u=0.0045). The comparison group had no statistically significant differences when compared with the control group (pm-u=0.9979). Insulin therapy for 31 days increases the concentration of VEGF-A in the intraocular fluid of rats with alloxan model of diabetes mellitus.

A polyphenol-metal nanoparticle platform for tunable release of liraglutide to improve blood glycemic control and reduce cardiovascular complications in a mouse model of type II diabetes

Liraglutide is a GLP-1 receptor agonist recently approved for Type-II diabetes (T2D) treatment with superior hypoglycemic effect while also improving cardiovascular function for the patients. However, its application has been limited by its short half-life (~13 h), which requires daily injections to maintain effective drug concentrations in blood, thus increasing the risk of poor patient compliance and complications. In this study, we developed a ternary liraglutide/tannic acid (TA)/Al3+ nanoparticle system based on hydrogen bond formation between liraglutide and TA and stabilized by complex coordination interaction between TA and Al3+. This ternary nanoparticle formulation offers sustained release of liraglutide for >8 days by optimizing the concentration of TA during nanoparticle assembly. A flash nanocomplexation (FNC) process was adopted to confer homogeneous mixing of the three components and control the assembly kinetics, thus enabling efficient encapsulation, a tunable drug release profile, improved nanoparticle size uniformity, and a high degree of colloidal stability. Upon a single intraperitoneal (i.p.) administration, the optimized formulation effectively lowered the high blood glucose level in a T2D db/db mice model to the normal range (8–10 mmol/L) within 6 h, maintained it for 60 more hours, and kept it lower than the original level for >6 days. In a 30-day treatment study, the nanoparticle formulation with a dosage frequency of once every 5 days exhibited similar or better control of blood sugar level (20% reduction in HbA1c) and weight control than daily injection of free liraglutide at the same treatment dose. The extended glycemic control led to distinctive improvements on reducing cardiomyopathy, including inhibition in lipo-toxicity by decreasing 40% of triglyceride, 30% of diacylglycerol and 50% of PKC level in the heart, as well as ameliorating oxidative stress and cell apoptosis activities through positive regulation on superoxidase, malondialdehyde, caspase-3 and Bax. This nanoparticle system demonstrates improved therapeutic potential owing to its long-acting glycemic control with improved cardiovascular function and reduced tissue toxicity in multiple organs.

GC-MS Analysis and Attenuation of Bleomycin-Induced Lung Fibrosis by Fractionated Methanolic Extract of Cissampelos Owariensis in Wistar Rats

ABSTRACTCrude methanolic leaf extract of Cissampelos owariensis was fractionated using vacuum liquid chromatography and analyzed by gas chromatography–mass spectrometry (GC-MS). Male Wistar rats were induced pulmonary fibrosis (PF) by a single intraperitoneal administration of 0.75 U 100 g−1 bleomycin (BLM), divided equally into four groups and given orally fresh water (control), 10 mg kg−1 quercetin, 200, or 400 mg kg−1 crude methanol leaf extract (crudemet) of C. owariensis daily for 28 d. Plasmatic enzymes, antioxidants, and lipid peroxidation (LPO) were determined spectrophotometrically, and the histology of lung section was done microscopically. GC-MS revealed the presence of hexadecanoic, phytol, 9,12-octadecadienoic acid (z,z)-methyl ester. Lung fibrosis increased the plasmatic total protein and alkaline phosphatase (ALP) activities. The BLM-administered rats showed decreased sodium dismutase (SOD), glutathione (GSH) activity, and alveolar hyperplasia. Oral administration of crudemet of C. owariensis ameliorated total protein, ALP activity, and LPO levels. The bioactive agents present in the C. owariensis extract may have the potential of reducing pathophysiology through increased antioxidants, thereby reducing BLM-induced lung hyperplasia.

Cardiotonic Steroids Induce Vascular Fibrosis Via Pressure-Independent Mechanism in NaCl-Loaded Diabetic Rats.

Endogenous cardiotonic steroid, marinobufagenin (MBG), induces Fli1-dependent tissue fibrosis. We hypothesized that an increase in MBG initiates the development of aortic fibrosis in salt-loaded rats with type 2 diabetes mellitus (DM2) via pressure-independent mechanism. DM2 was induced by a single intraperitoneal administration of 65 mg/kg streptozotocin to neonatal (4-5 days) male Wistar rats. Eight-week-old DM2 rats received water or 1.8% NaCl (DM-NaCl) solution for 4 weeks (n = 16); half of DM-NaCl rats were treated with anti-MBG monoclonal antibody (mAb) (DM-NaCl-AB) during week 4 of salt loading; control intact rats received water (n = 8/group). Blood pressure, MBG, erythrocyte Na/K-ATPase activity, aortic weights, levels of fibrosis markers (Fli1, protein kinase Cδ, transforming growth factor-β1, receptors of the transforming growth factor beta5, fibronectin, collagen-1), and sensitivity of the aortic explants to the vasorelaxant effect of sodium nitroprusside were assessed. No changes in systolic blood pressure were observed while erythrocyte Na/K-ATPase was inhibited by 30%, plasma MBG was doubled, and aortic markers of fibrosis became elevated in DM-NaCl rats versus control. Treatment of DM-NaCl rats with anti-MBG mAb activated Na/K-ATPase, prevented increases in aortic weights, and the levels of fibrosis markers returned to the control levels. The responsiveness of the aortic rings from DM-NaCl rats to the relaxant effect of sodium nitroprusside was reduced (half maximal effective concentration (EC50) = 29 nmol/L) versus control rings (EC50 = 7 nmol/L) and was restored by anti-MBG mAb (EC50 = 9 nmol/L). Our results suggest that in salt-loaded diabetic rats, MBG stimulates aortic collagen synthesis in a pressure-independent fashion and that 2 profibrotic mechanisms, Fli1 dependent and transforming growth factor-β dependent, underlie its effects.

New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.

92 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared 1) the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs, 2) the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 induced significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report of an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.

Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats

Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity – a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.

Nephroprotective effect of green tea, rosmarinic acid and rosemary on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute renal toxicity in Wistar rats.

The present study was designed to investigate the chemoprotective effect of green tea extract (GTE), rosmarinic acid (RA) and rosemary extract (RE) against diethylnitrosamine (DEN) initiated and ferric nitrilotriacetate (Fe-NTA) promoted nephrotoxicity in rats. Forty male rats were categorized into five: Group I included healthy rats, group II received DEN+Fe-NTA, group III received 200 mg/kg b.wt. of RE+DEN+Fe-NTA, group IV received 1 g/kg b.wt. of GTE+DEN+Fe-NTA and group V received 50 mg/kg b.wt. of RA+DEN+Fe-NTA. RE, GTE, RA were given orally for 14 days before single intraperitoneal administration of DEN (160 mg/kg) till the end of the experiment. Eighteen days after DEN, a single intraperitoneal dose of Fe-NTA (5 mg Fe/kg) was administrated to rats to promote nephrotoxicity. The biochemical parameters were analyzed in serum at time intervals while the malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were assessed in both serum and renal tissues. Kidney from each group was histopathologically examined at time intervals. The administration of Fe-NTA after DEN dose to albino rats resulted in acute nephrotoxicity which was characterized by a highly significant elevation of serum urea, creatinine, uric acid (p=0.000), serum and renal MDA and TNF-α (p=0.000) with vacuolation of epithelial lining renal tubules. The administration of RE, GTE and RA prior to DEN+Fe-NTA treatment significantly ameliorated the observed increased levels of the above mentioned parameters. GTE, RA & RE exerted a protective effect against renal toxicity with GTE showing a more pronounced effect on renal function parameters while RA showed the best antioxidant impact.

Morphological characteristics of the visual cortex in experimental diabetes mellitus.

Background. The medical and social problem of diabetes mellitus (DM) is due to the significant prevalence, early disability and death of patients due to specific complications, one of which is diabetic encephalopathy. According to scientific literature, the latter is diagnosed in 80.7% of patients with type 1 diabetes. Objective of our work was to establish histo-ultrastructural changes in the visual cortex on the 56th day of the development of streptozotocinin-induced diabetes mellitus (SSD). Methods. For the study, 10 sexually mature white male rats (body weight 160-180 g) were used, which were equally divided into 2 groups: the first was a research one with SDS (single intraperitoneal administration of streptozotocin (SIGMA Chemical USA) at a rate of 6 mg / 100 g weight body), the second - control. For morphometric studies, the NIH USA “Image J” software and the statistical package Stat.Soft.Inc were used; Tulsa, OK, USA; Statistica 10. Results. In animals with SJS, in contrast to the control group of rats, the number of vacuolated and pycnomorphic neurons increases against the background of a decrease in normochromic neurons by 0.01 mm2 of the visual cortex. At the same time, the glial index increases by 1.8 times, and the number of capillaries by 0.01 mm2 decreases by 2.2 times. At the ultrastructural level, the most pronounced changes are experienced by pycnomorphic neurons, which are localized in the inner pyramidal layer. In the outer pyramidal and inner granular layers of the visual cortex, neurons with partial necrosis are found. Such changes in the visual cortex occur against the background of the development of diabetic microangiopathy. Thus, on day 56 of the course of SJS in the visual cortex of rats, diabetic encephalopathy is diagnosed, which is morphologically manifested: an increase in the numerical density of pycnomorphic and vacuolated neurons due to a decrease in normochromic neurons; phenomena of satellite disease and neuronophagy; axonopathy in tangential bundles of nerve fibers of the neuropil. Conclusion. Such changes occur against the background of the development of diabetic microangiopathy, which is characterized by: erythrocyte sludge, platelet adhesion and microthrombi in the lumen of microvessels; an increase in the capillary wall area with a decrease in the area of their lumen; thickening of the basement membrane; pericapillary edema of the legs of astrocytes.

Adaptations induced by lacking maternal Kinin B1 receptor and maternal swimming during pregnancy in the placenta and in fetal growth

Dopamine and glutamate play critical roles in the reinforcing effects of cocaine. We demonstrated that a single intraperitoneal administration of cocaine induces a significant decrease in [3H]-d-aspartate uptake in the pre-frontal cortex (PFC). This decrease is associated with elevated dopamine levels, and requires dopamine D1-receptor signaling (D1R) and adenylyl cyclase activation. The effect was observed within 10 min of cocaine administration and lasted for up to 30 min. This rapid response is related to D1R-mediated cAMP-mediated activation of PKA and phosphorylation of the excitatory amino acid transporters EAAT1, EAAT2 and EAAT3. We also demonstrated that cocaine exposure increases extracellular d-aspartate, l-glutamate and d-serine in the PFC. Our data suggest that cocaine activates dopamine D1 receptor signaling and PKA pathway to regulate EAATs function and extracellular EAA level in the PFC.

Binding Immunoglobulin Protein (BIP) Inhibits TNF-α-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model.

ObjectiveThe association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro.Methods hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry.ResultsBiP‐treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c‐Fms and Receptor Activator of NF‐κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen–activated protein kinases, extracellular signal–regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c‐Fos and NFATc1. BiP directly inhibited TNF‐α– or Receptor Activator of NF–κB Ligand (RANKL)–induced NF‐κB nuclear translocation in THP‐1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways.ConclusionBiP combines an anti‐inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.

Therapeutic Effect of Yttrium Oxide Nanoparticles for the Treatment of Fulminant Hepatic Failure

Aim: To explore the potential therapeutic effect of yttrium oxide nanoparticles (Y2O3 NPs) on fulminant hepatic failure. Materials & methods: RAW264.7 cells and a lipopolysaccharide/D-galactosamine-induced hepatic failure murine model were used to assess the effects of Y2O3NPs. Results: Y2O3 NPs exhibited anti-inflammatory activity by scavenging cellular reactive oxygen species and dampening reactive oxygen species-mediated NF-κB activation in vitro. A single intraperitoneal administration of Y2O3 NPs (30mg/kg) enhanced hepatic antioxidant status and reduced oxidative stress and inflammatory response in lipopolysaccharide/galactosamine-induced mice. Y2O3 NPs also attenuated hepatic NF-κB activation, cell apoptosis and liver injury. Conclusion: Y2O3 NP administration could be used as a novel therapeutic strategy for treating fulminant hepatic failure and oxidative stress-related diseases.

In vitro and in vivo toxicity of pristine C60 fullerene aqueous colloid solution

Toxicity of the C60 fullerene aqueous colloid solution in vitro and in vivo experiments was studied. C60 fullerene in the concentration range of 3.6–144 µg/mL demonstrated low toxicity against human embryonic kidney (HEK293) cells with 383.4 μg/mL IC50 value. The acute toxicity of C60 fullerene in a dose progression (75, 150, 300, 600, 1200 and 1800 mg/kg) was investigated at 14th day after single intraperitoneal (i.p.) administration into mice. No toxic effect of С60 fullerene in the dose range of 75–150 mg/kg was observed; the calculated LD50 value was 721 mg/kg. The toxic effect of C60 fullerene was observed at a concentration of 300 mg/kg and higher, it was accompanied with mice behavior disturbance, hematotoxicity and pathomorphological changes in spleen, hepatic and kidney tissues. In mice treated with 600 mg/kg of C60 fullerene indices of inflammatory process were detected, whereas at 1200 mg/kg dose leukopoies and thrombocytopoies were found to be suppressed. Thus, C60 fullerene aqueous colloid solution in a dose range of 75–150 mg/kg is nontoxic and could be used for biomedical purposes.

ACUTE TOXICITY OF CERIUM DIOXIDE NANOPARTICLES

The resorptive effects of 0.01 M cerium nanodioxide sol upon single intraperitoneal administration to rats have been studied. The acute exposure to nanoparticles was found to have a dose-dependent general toxic effect on the body (weight loss, inflammatory changes in the abdominal organs, modification of individual behavior, hematological changes, metabolic imbalance), which develops on the background of POL activation. The prooxidant effect of cerium dioxide nanoparticles is demonstratively manifested at relatively high exposure levels (80–8 mg / kg). The threshold dose for the general toxic effect (Limch integr) is equal to 0.8 mg / kg.

Antidiabetic activity of corn steep liquor extract of Curculigo pilosa and its solvent fractions in streptozotocin-induced diabetic rats

The rhizome of Curculigo pilosa (CP) prepared with Corn steep liquor (CSL), is traditionally used in the treatment of diabetes mellitus. In this study, antidiabetic activity of the CSL extract and its fractions (butanol and methanol) were evaluated in streptozotocin-induced diabetic rats. Diabetes mellitus was induced by single intraperitoneal administration of streptozotocin (50 mg/kg) and diabetic rats were treated with 300 mg/kg bodyweight of the extract(s) for 28 days. Antidiabetic effect was monitored by plasma blood glucose, oral glucose tolerances test (OGGT), body weight and heamatological indices. Also serum urea, creatinine, cholesterol, high density lipoprotein, bilirubin, alkaline phosphatase, aspartate and alanine transaminases were evaluated. The levels of hepatic glutathione, catalase, superoxide dismutase, lipid peroxidation, nitric oxide and hydrogen peroxide were assessed; also histopathology of the hepatic tissues was examined. Oral administration of the extract resulted in significant (p < 0.05) reduction of plasma blood glucose (29.32% crude extract and 22.96% butanol fraction) and also increased body weight (20.61% crude extract, 13.44% butanol fraction and 6.23% methanol fraction) of diabetic rats. The heamotogical indices, plasma parameters and hepatic oxidative stress in diabetic rats were returned to near normalcy following treatment with the extract(s). The GC-MS analysis of the extract revealed the presence of stilbene, a proven antidiabetic agent, which might be responsible for the antidiabetic activity. The results obtained suggest that the CSL extract of CP could be used in management of diabetes mellitus thus providing scientific validation of its use as an antidiabetic agent.

TAK-137, an AMPA receptor potentiator with little agonistic effect, produces antidepressant-like effect without causing psychotomimetic effects in rats

Ketamine produces a rapid-onset antidepressant effect in patients with treatment-resistant depression (TRD), although it concurrently causes undesirable psychotomimetic side effects. Accumulating evidence suggests that ketamine produces antidepressant effects via activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R), with consequent activation of the mammalian target of rapamycin (mTOR) pathway and up-regulation of brain-derived neurotrophic factor (BDNF). We previously reported that TAK-137, an AMPA-R potentiator with little agonistic effect, had potent procognitive effects with lower risks of bell-shaped dose-response and seizure induction. In this study, we characterized the potential of TAK-137 as a novel antidepressant in rats. In rat primary cortical neurons, TAK-137 increased the phosphorylated form of Akt, extracellular signal-regulated kinase, mTOR, and p70S6 kinase, and dose-dependently increased the expression level of BDNF protein. The antidepressant-like effects of ketamine and TAK-137 were assessed on the day after final administration using the novelty-suppressed feeding test in rats. A single intraperitoneal administration of ketamine shortened the latency to feed. Under these conditions, oral administration of TAK-137 for 3 days shortened the feeding latency. Ketamine induced hyperlocomotion and reduced prepulse inhibition, which may be associated with psychotomimetic effects, while TAK-137 did not. TAK-137 may be a safer and rapid-onset therapeutic drug for the treatment of major depressive disorder, including TRD.

New generation of oncolytic herpesviruses embodying immunotherapeutic genes encoding IL-12 and anti-PD-1 antibody.

e14250 Background: Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpes simplex viruses (oHSV) have a major impact on cancer therapy marred by rare failures of healthy organs. Methods: We constructed 3 families of recombinant oHSVs expressing no immunomodulatory genes (T1 series), murine or human IL-12 (T2 series) and murine or human IL-12 and anti-PD-1 antibody (T3 series). We compared the oncolytic effects of a single or multiple intratumoral injection(s) of T1, T2 and T3 series oHSVs. We also compared the effectiveness of intratumoral injection of T3 oHSV with systemic administration of anti PD-1 ab and IL12 alone or in combinations with T1. Results: Insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). In syngeneic mice the T3 series oHSV expressing murine IL-12 and PD-1 Ab was effective against a variety of murine tumors. Concurrent with enhanced cytolytic activity the T3 oHSV induced the production and significant intratumoral accumulation of IL-12, PD-1 Ab and IFN-γ. Consistent with an earlier report we noted an inverse correlation between the volume of the tumor and the quantity of retained IFN-γ. The most effective oncolytic effect resulted from the administration of T3855 expressing both IL12 and anti PD-1 antibody or T2850 concurrently with intraperitoneal administration of anti PD-1 antibody alone. The least effective were single intraperitoneal administration of IL12 or PD-1 antibody. Intratumoral injection of T3 oHSV was most effective against murine tumors in comparison of either systemic administration of anti PD-1 ab and IL12 or intratumoral injection of T1 in combinations of systemic administration of anti PD-1 ab and IL12. Conclusions: We report the marriage in a single therapeutic agent of three distinct cancer therapies: the targeting of cancer cells by oncolytic viruses, the stimulation of immune system by IL12, and the production of immunotherapeutic antibodies against PD-1. The significant finding reported in this article is that the anti-tumor responses remain concentrated in the tumor environment.

Antisense Oligonucleotides Immobilized on Silicon-Organic Nanoparticles as a Tool for Prolonged Correction of Hypertensive States.

We propose an original method for controlling BP by administration of Si~ODN nanocomposites containing antisense oligonucleotides fixed on silicon-organic nanoparticles. ODN in nanocomposites are targeted to mRNA of the genes encoding angiotensin-converting enzyme (ACE1) and type 1 angiotensin-II receptor (AT1A). The experiments were performed on hypertensive ISIAH rats, a genetic model of hypertension. Single inhalation or intraperitoneal administration of the nanocomposites targeted to ACE1 mRNA or ATA1 mRNA, respectively, led to a pronounced decrease (by ~30 mm Hg) in systolic BP in ISIAH rats over a week. The use of scrambled ODN in the nanocomposites had no effect. A decrease in the expression of ACE1 and AT1A genes under the effect of the corresponding antisense ODN was demonstrated, which attested to directed effect of the test preparations.

Assessment of the structural reorganization of liver and biochemical parameters of blood serum after introduction of zinc nanoparticles and its oxides.

The demand for nanoparticles of metals and their oxides in medicine and biology is indisputable. To ensure the safe use of the unique capabilities of nanostructures, in particular, essential metals and their oxides, and to further search for ways leveling side effects of toxic effects in biomedical applications, a multifaceted approach to the study of their properties is needed, primarily affecting the effects on the organism level. In this connection, the purpose of the present research was to study the effect of zinc nanoparticles (ZnNPs) and zinc oxide nanoparticles (ZnONPs) on structural reorganization of the liver and morpho-biochemical parameters of rat blood. The test substances exhibit a hepatotoxic effect upon their single intraperitoneal administration to rats. In the experiment, increased activity of gamma glutamyltransferase (GGT) and lactate dehydrogenase (LDH), increased expression of caspase-3, the presence of signs of oxidative stress, inflammation, and capillary-trophic insufficiency, and induction of tumor necrosis factor (TNF-α), and colony stimulating factor 2 (granulocyte-macrophage) (GM-CSF) were registered in the experiment. The level of interferon-γ in the experimental groups tended to decrease in comparison with the control group. The observed effects progressed in time, most noticeably manifested in the case of ZnONPs. Comparing the dosages, ZnNPs are less toxic than ZnONPs.

Liposomal Curcumin is Better than Curcumin to Alleviate Complications in Experimental Diabetic Mellitus.

Curcumin (CC) is known to have anti-inflammatory and anti-oxidative properties and has already been tested for its efficiency in different diseases including diabetes mellitus (DM). New formulations and route administration were designed to obtain products with higher bioavailability. Our study aimed to test the effect of intraperitoneal (i.p.) administration of liposomal curcumin (lCC) as pre-treatment in streptozotocin(STZ)-induced DM in rats on oxidative stress, liver, and pancreatic functional parameters. Forty-two Wistar-Bratislava rats were randomly divided into six groups (seven animals/group): control (no diabetes), control-STZ (STZ-induced DM —60 mg/100g body weight a single dose intraperitoneal administration, and no CC pre-treatment), two groups with DM and CC pre-treatment (1mg/100g bw—STZ + CC1, 2 mg/100g bw—STZ + CC2), and two groups with DM and lCC pre-treatment (1 mg/100g bw—STZ + lCC1, 2 mg/100g bw—STZ + lCC1). Intraperitoneal administration of Curcumin in diabetic rats showed a significant reduction of nitric oxide, malondialdehyde, total oxidative stress, and catalase for both evaluated formulations (CC and lCC) compared to control group (p < 0.005), with higher efficacy of lCC formulation compared to CC solution (p < 0.002, excepting catalase for STZ + CC2vs. STZ + lCC1when p = 0.0845). The CC and lCC showed hepatoprotective and hypoglycemic effects, a decrease in oxidative stress and improvement in anti-oxidative capacity status against STZ-induced DM in rats (p < 0.002). The lCC also proved better efficacy on MMP-2, and -9 plasma levels as compared to CC (p < 0.003, excepting STZ + CC2 vs. STZ + lCC1 comparison with p = 0.0553). The lCC demonstrated significantly better efficacy as compared to curcumin solution on all serum levels of the investigated markers, sustaining its possible use as adjuvant therapy in DM.