Intraperitoneal Injection Of Saline Research Articles

Establishment of animal models of epidermal growth factor receptor inhibitor-related rashes

To establish animal models epidermal growth factor receptor inhibitor-related skin rashes using cetuximab, gefitinib or erlotinib. Female SCID mice were randomly divided into blank control group and high-, moderate-, and low-dose cetuximab groups. The mice in control group received intraperitoneal injection of saline, and those in the 3 cetuximab groups were injected with 80, 40, and 20 mg/kg cetuximab (3 times a week for 4 weeks), respectively. The general skin appearance and skin pathologies of the mice were observed. Female BN rats were randomly divided into blank group, ovalbumin group, gefitinib group and erlotinib group, and in the latter 3 groups, the rats were given ovalbumin (1 mg), gefitinib (37.5 mg/kg), and erlotinib (23.5 mg/kg) by lavage once daily for 45 days, respectively. Skin pathologies of the rats were observed, and serum levels of TNF-α, IL-6 and other inflammatory factors were detected using ELISA. Intraperitoneal injection of cetuximab did not induce typical skin rashes, scabs or obvious skin inflammation in the mice. In female BN rats, lavage of gefitinib caused obvious skin rashes, scabs and exudation, and obvious inflammatory cell infiltration, keratinosis, spinous layer release and epidermal thickening were observed in the skin. No obvious skin inflammation were observed in the rats in the control, ovalbumin or erlotinib groups. While IgE (P=0.061) and TNF-α concentrations (P=0.057) did not differ significantly among the groups, serum levels of IL-6 was significantly higher in gefitinib group than in the blank control group (P=0.016) but similar between erlotinib group and the blank group (P=0.910). Intraperitoneal injection of cetuximab can not induce epidermal growth factor receptor inhibitor-related skin rashes in SCID mice. Lavage of gefitinib, but not erlotinib, can be used to establish models of epidermal growth factor receptor inhibitor-related rashes in BN rats.

Antitumor effects of Auraptene in 4T1 tumor-bearing Balb/c mice.

Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. There was no significant change in body weight in all animal groups before and after treatment. 10days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8+Tcell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

Cognitive impairment resulting from treatment with docetaxel, doxorubicin, and cyclophosphamide

Breast cancer is the most commonly diagnosed cancer among women and it is estimated that about 30% of newly diagnosed cancers in women will be breast cancers. While advancements in treating breast cancer have led to an average 5-year survival rate of 90%, many survivors experience cognitive impairments as a result of chemotherapy treatment. Doxorubicin, cyclophosphamide, and docetaxel (TAC) are commonly administered as breast cancer treatments; however, there are few studies that have tested the cognitive effects of TAC. In the current study, 12-week-old female C57BL/6 mice received 4 weekly intraperitoneal injections of either saline or a combination therapy of doxorubicin and cyclophosphamide followed by 4 weekly docetaxel injections. Four weeks after the last injection, mice were tested for hippocampus-dependent cognitive performance in the Y-maze and the Morris water maze. During Y-maze testing, mice exposed to TAC exhibited impairment. During the water maze assessment, all animals were able to locate the visible and hidden platform locations. However, mice that received the TAC presented with a significant impairment in spatial memory retention on the probe trial days. TAC treatment significantly decreases the dendritic complexity of arborization in the dentate gyrus region of the hippocampus. In addition, comparative proteomic analysis revealed downregulation of proteins within key metabolic and signaling pathways associated with cognitive dysfunction, such as oxidative phosphorylation, ephrin signaling, and calcium signaling.

Protective role of Oleuropein, an olive tree secoiridoid and its acyl-derivate in experimental models of rheumatic diseases

Oleuropein (OL), an olive tree secoiridoid, and its peracetylated derivate (Per-OL) have exhibited several beneficial effects reducing acute inflammatory responses on LPS-stimulated macrophages. The present study was designed to evaluate the effects of both dietary OL and Per-OL supplementations on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with 0.05% (w/w) OL, 0.05% or 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and mice received a booster injection on day 21. Mice were sacrificed 42 days after first immunization. Then, blood was recollected and paws were histological and biochemically processed. OL and Per-OL experimental diets significantly prevented histological damage and arthritic score development in RA. In addition, serum collagen oligomeric matrix protein (COMP) and metalloproteinase 3 (MMP)-3 as well as proinflammatory cytokines levels in paw homogenates (including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and interferon (IFN)-γ were significantly ameliorated in those animals fed with dietary secoiridoids. Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with OL and Per-OL diets. These results reveal, for the first time, the anti-inflammatory effect of a diet supplemented with OL and Per-OL in an experimental murine model of CIA, which was accompanied by a significant reduction in the pro-inflammatory markers studied (COMP, MMP-3, TNF-α, IL-1β, IL-6, IL-17 and IFN-γ). The mechanisms involved could be related to an activation of the antioxidant pathway Nrf2/HO-1 and an inhibition of MAP kinases and NF-κB signaling pathways activations. On the other hand, we studied the effects of both OL and Per-OL diets supplemented diets in a model of pristane-induced systemic lupus erythematosus (SLE) in BALB / c mice. Mice received an intraperitoneal injection of pristane or saline according to the experimental groups and were fed with experimental diets enriched with OL and Per-OL. Changes in cytokines levels and pro-inflammatory markers were evaluated by the ELISA assay. Changes in the protein expression of inducible nitric oxide synthase (iNOS), microsomal prostaglandin E synthase 1 (mPGEs-1) as well as HO-1, nuclear factor Nrf2, p38 protein kinases, C-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), signal transduction factor and activator of transcription (STAT) -3, NF-κB and inflammasome NLRP3 activation were determined using the Western Blot. Both OL and Per-OL dietary treatments significantly reduced kidney damage and reduced serum MMP-3 and renal prostaglandin E2 (PGE2) levels. Our studies indicated that OL and Per-OL enriched diets produced an increase in the expression of the antioxidant pathway Nrf2 / HO-1 which was accompanied by a decrease in the activation of the Janus kinases and signal transducer and activator of transcription (JAK / STAT), MAPKs, NF-κB and inflammasome NLRP3 proteins. In conclusion, dietary supplementation with OL and Per-OL could serve as the basis for the development of new nutritional strategies for the prevention of RA. In addition, these results also suggest that dietary supplementation with OL and Per-OL could constitute a new alternative therapeutic approach as a preventive or palliative of nephritis in the management of SLE.

Interaction of maternal immune activation and genetic interneuronal inhibition

Genes and environment interact during intrauterine life, and potentially alter the developmental trajectory of the brain. This can result in life-long consequences on brain function. We have previously developed two transgenic mouse lines that suppress Gad1 expression in parvalbumin (PVALB) and neuropeptide Y (NPY) expressing interneuron populations using a bacterial artificial chromosome (BAC)-driven miRNA-based silencing technology. We were interested to assess if maternal immune activation (MIA), genetic interneuronal inhibition, and the combination of these two factors disrupt and result in long-term changes in neuroinflammatory gene expression, sterol biosynthesis, and acylcarnitine levels in the brain of maternally exposed offspring. Pregnant female WT mice were given a single intraperitoneal injection of saline or polyinosinic–polycytidilic acid [poly(I:C)] at E12.5. Brains of offspring were analyzed at postnatal day 90. We identified complex and persistent neuroinflammatory gene expression changes in the hippocampi of MIA-exposed offspring, as well in the hippocampi of Npy/Gad1 and Pvalb/Gad1 mice. In addition, both MIA and genetic inhibition altered the post-lanosterol sterol biosynthesis in the neocortex and disrupted the typical acylcarnitine profile. In conclusion, our findings suggest that both MIA and inhibition of interneuronal function have long-term consequences on critical homeostatic mechanisms of the brain, including immune function, sterol levels, and energy metabolism.

The possible protective effect of aldehyde dehydrogenase 2 agonist (Alda-1) on doxorubicin induced toxicity of the left ventricular cardiomyocytes of adult male mice.

ABSTRACTBackground: Doxorubicin (DOX) is an effective antineoplastic drug. However, its cardiotoxicity is a major obstacle that limit its use. Therefore, a novel protective agent is urgently needed. Enzyme activation recently gained much interest as a new therapeutic strategy. In this context, Alda-1 is a newly emerged molecule in the field of cardioprotection through its activation of aldehyde dehydrogenase 2 enzyme.Aim of the study: To evaluate the possible protective effect of aldehyde dehydrogenase agonist Alda-1 on doxorubicin induced cardiotoxicity. Material and methods: Twenty-four adult male C57BL/6 mice were divided equally into 4 groups. Group I received intraperitoneal injection of saline. Group II received intraperitoneal injection of Alda-1 (10 mg/kg) daily for 5 days. Group III received a single intraperitoneal injection of DOX (20 mg/kg). Group IV received both DOX and Alda-1 in the same regimen as in groups II and III, Alda-1 was administered 1 day before DOX. All mice were euthanized on the 5th day following DOX administration. Blood samples were collected, hearts were excised and further processed for anatomical, histological and biochemical analysis.Results: DOX administration caused extensive cardiotoxicity as evident by the marked decrease in the heart weight and the extensive myocardial lesions shown by the light and electron microscopic examination. Moreover, biochemical serum markers of cardiac injury (CK-MB &LDH) was markedly elevated. Increased oxidative stress was also encountered as shown by the decreased serum TAC and increased tissue MDA. Furthermore, mitochondrial morphometry showed increased mitochondrial size. However, concomitant administration of Alda-1 with DOX have markedly alleviated the heart injury as shown by the restoration of the heart weight and cardiac architecture together with preservation of the mitochondrial structure. Moreover, Alda-1 has ameliorated the biochemical markers of cardiac injury and the oxidative stress.Conclusion: Alda-1 provides a valuable protective effect against doxorubicin triggered cardiotoxicity.

A Long-Term Enriched Environment Ameliorates the Accelerated Age-Related Memory Impairment Induced by Gestational Administration of Lipopolysaccharide: Role of Plastic Mitochondrial Quality Control.

Studies have shown that gestational inflammation accelerates age-related memory impairment in mother mice. An enriched environment (EE) can improve age-related memory impairment, whereas mitochondrial dysfunction has been implicated in the pathogenesis of brain aging. However, it is unclear whether an EE can counteract the accelerated age-related memory impairment induced by gestational inflammation and whether this process is associated with the disruption of mitochondrial quality control (MQC) processes. In this study, CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS, 50 μg/kg) or normal saline (CON group) during gestational days 15–17 and were separated from their offspring at the end of normal lactation. The mothers that received LPS were divided into LPS group and LPS plus EE (LPS-E) treatment groups based on whether the mice were exposed to an EE until the end of the experiment. At 6 and 18 months of age, the Morris water maze test was used to evaluate spatial learning and memory abilities. Quantitative reverse transcription polymerase chain reaction and Western blot were used to measure the messenber RNA (mRNA) and protein levels of MQC-related genes in the hippocampus, respectively. The results showed that all the aged (18 months old) mice underwent a striking decline in spatial learning and memory performances and decreased mRNA/protein levels related to mitochondrial dynamics (Mfn1/Mfn2, OPA1, and Drp1), biogenesis (PGC-1α), and mitophagy (PINK1/parkin) in the hippocampi compared with the young (6 months old) mice. LPS treatment exacerbated the decline in age-related spatial learning and memory and enhanced the reduction in the mRNA and protein levels of MQC-related genes but increased the levels of PGC-1α in young mice. Exposure to an EE could alleviate the accelerated decline in age-related spatial learning and memory abilities and the accelerated changes in MQC-related mRNA or protein levels resulting from LPS treatment, especially in aged mice. In conclusion, long-term exposure to an EE can counteract the accelerated age-related spatial cognition impairment modulated by MQC in CD-1 mother mice that experience inflammation during pregnancy.

467 Maternal dietary supplementation with pomegranate juice during lactation reduces offspring brain inflammatory response in mice

Pomegranates are considered a potent natural antioxidant. We hypothesized that maternal over-the-counter pomegranate juice (POM) consumption during lactation would attenuate inflammation-induced offspring brain injury. Six pregnant mice gave birth naturally at term. Following delivery from day 1 to 5, all dams were provided with standard chow. Of which, three dams were provided with ad libitum access to water (WAT), and the other 3 with diluted (1:5) POM juice. Pups were randomized into three groups: Control (CON), intraperitoneal injection of normal saline (NS), or lipopolysaccharide (LPS) 100 μg/kg, and creating six groups by taking two pups from each dam to 6 pups in each group. Pups were sacrificed 4 hours following the injection, weighed, and the brains processed for further analyses. The serum’s protein level of IL6; The brain’s protein level of NFκB, neuronal nitric oxide synthase (nNOS), IL6, and TNFα, were determined by ELISA and Western blot. The offsprings’ weight on their 5th day of life in the POM arm was significantly lower compared to the WAT arm (FigA1). Serum IL6 levels in the POM-CON group were significantly increased compared to pups of the WAT-CON. LPS administration increased pups’ serum IL6 level to a greater degree in the POM than the WAT arm (FigA2). The pups’ brain protein levels of TNFα, IL6, and NFκB of the CON and NS groups of the POM arm were significantly increased compared to pups of the WAT arm. LPS significantly increased pups’ brain protein levels of TNFα IL6 and NFκB within the WAT groups. However, surprisingly, LPS significantly decreased pups’ brain inflammation in the POM group (FigB). A maternal enriched diet with POM during lactation led to low offspring weight and unexpectedly elevated baseline serum and brain inflammation markers. However, it attenuated offspring brain inflammation following LPS induced inflammation. These results suggest that reduced growth in POM offsprings might have contributed to the increased basal inflammation, while maternal POM consumption reduces offspring brain inflammatory response to LPS.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Citicoline improved cardiovascular function in animal model of dysautonomia.

The autonomic nervous system controls cardiovascular function. Autonomic dysfunction or dysautonomia is commonly encountered in several diseases like Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a chemical that changes into the neurotoxin MPP+, which causes catecholamine depletion. We aimed to study the effects of citicoline on cardiovascular function in MPTP-treated albino rats. Twenty-four male albino rats were divided into four groups (6 rats/group): negative control received intraperitoneal (i.p.) saline injection for five consecutive days, a positive control (Citicoline group) received citicoline (250 mg/kg) by oral gavage for consecutive 20 days, MPTP treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days, MPTP + citicoline treated with MPTP-HCL (30 mg/kg, i.p.) for five consecutive days followed by treatment with oral doses of citicoline (250 mg/kg) for 20 days. Cardiovascular functions evaluated through recording electrocardiogram (ECG), echocardiography, measuring arterial blood pressure and assessment of aortic rings vascular reactivity. Biochemical measurements on cardiac tissue for tyrosine hydroxylase, norepinephrine, glucose transporter 1 (GLUT1), insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ co-activator-1 (PPAR-γ co-activator-1) (PGC-1), phosphatase and tensin homolog-induced kinase 1 (PINK1), carnitine palmitoyltransferase I (CPT1), uncoupling protein 2 (UCP2) and adenosine monophosphate-activated protein kinase alpha 2 (AMPKα2). Citicoline increased cardiac norepinephrine and tyrosine hydroxylase and improved markers related to ROS scavenger, mitochondrial permeability, calcium homeostasis on the cellular level, metabolic homeostasis, and mitochondrial biogenesis. We conclude that citicoline improved cardiovascular dysautonomia and that was reflected on cardiac contractility, electrical activity, blood pressure, and vascular reactivity.

Protective effect of Tanshinone IIA on LPS-induced canine endometritis

Canine endometritis is a common disease in dogs. This work intends to establish the model of lipopolysaccharide (LPS) -induced canine endometritis, and investigate the effect of Tanshinone IIA (Tan IIA) on canine endometritis. At first, we tested the rectal temperature and the production of IL-1β and TNF-α at 6 h, 12 h, 18 h and 24 h after LPS administration. Then 9 beagles were divided into 3 groups on average, all beagles received intraperitoneal injection of saline solution (group 1 and 2) or Tan IIA (group 3) at 6 h before and after LPS challenge. Beagles of group 2 and 3 were performed uterine infusion of LPS, and beagles of group 1 were performed uterine infusion of saline solution. The rectal temperature was measured 6 h, 12 h, 18 h, 24 h post-LPS challenge, all uterus were collected after 24 h post-LPS challenge. The results showed that canine endometritis can be established by LPS at the concentration of 0.5 mg/kg of body weight after 24 h performance. The rectal temperature, the production of IL-1β and TNF-α increased significantly when the model was established. The results showed that rectal temperature, production of IL-1β and TNF-α and the expression of IL-6 were significantly reduced after treatment with Tan IIA compared with the group of LPS challenge only. However, the expression of IL-10 increased after Tan IIA treatment. Considering the positive anti-inflammation effect on the LPS-induced canine endometritis, Tan IIA may be used as a therapeutic agent to treat the clinical canine endometritis.

Zinc Supplementation During Pregnancy Alleviates Lipopolysaccharide-Induced Glial Activation and Inflammatory Markers Expression in a Rat Model of Maternal Immune Activation.

Maternal immune activation (MIA) model has been profoundly described as a suitable approach to study the pathophysiological mechanisms of neuropsychiatric disorders, including schizophrenia. Our previous study revealed that prenatal exposure to lipopolysaccharide (LPS) induced working memory impairments in only male offspring. Based on the putative role of prefrontal cortex (PFC) in working memory process, the current study was conducted to examine the long-lasting effect of LPS-induced MIA on several neuroinflammatory mediators in the PFC of adult male pups. We also investigated whether maternal zinc supplementation can alleviate LPS-induced alterations in this region. Pregnant rats received intraperitoneal injections of either LPS (0.5mg/kg) or saline on gestation days 15/16 and supplemented with ZnSO4 (30mg/kg) throughout pregnancy. At postnatal day 60, the density of both microglia and astrocyte cells and the expression levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP were evaluated in the PFC of male pups. Although maternal LPS treatment increased microglia and astrocyte density, number of neurons in the PFC of adult offspring remained unchanged. These findings were accompanied by the exacerbated mRNA levels of IL-6, IL-1β, iNOS, TNF-α, NF-κB, and GFAP as well. Conversely, prenatal zinc supplementation alleviated the mentioned alterations induced by LPS. These findings support the idea that the deleterious effects of prenatal LPS exposure could be attenuated by zinc supplementation during pregnancy. It is of interest to suggest early therapeutic intervention as a valuable approach to prevent neurodevelopmental deficits, following maternal infection. Schematic diagram describing the experimental timeline. On gestation days (GD) 15 and 16, pregnant dams were administered with intraperitoneal injections of either LPS (0.5mg/kg) or vehicle and supplemented with ZnSO4 (30mg/kg) throughout pregnancy by gavage. The resulting offspring were submitted to qPCR, immunostaining, and morphological analysis at PND 60. Maternal zinc supplementation alleviated increased expression levels of inflammatory mediators and microglia and astrocyte density induced by LPS in the PFC of treated offspring. PND postnatal day, PFC prefrontal cortex.

Влияние интерлейкинов на сокращения мышцы трахеи и бронхов крысы

The article considers the role of IL-1β, IL-4, IL-8 and IL-13 in contractile activity of smooth muscles of trachea and bronchi. Studies were conducted on isolated preparations with using of electrical stimulation of the postganglionic nerves (frequency – 30 stimules/s, duration – 0,5 ms, amplitude – 20 V, duration of stimulation – 10 s.). Two groups of animals were formed: a control group (received an intraperitoneal injection of saline solution) and an experimental group with bronchial asthma (received an intraperitoneal injection of ovalbumin with its repeated administration after 14 days). Further, the tracheal and bronchi muscle contraction was evaluated after repeated ovalbumin administration and after perfusion with interleukin solutions. The study found that IL-4, IL-8 and IL-13 lead to a large increase in contractile responses of the smooth muscle of the trachea and bronchi both in the control group of animals and in the group of animals with ovalbumin-induced bronchial asthma. IL-1β leads to a relaxation effect on the tracheal and bronchi muscle in conditions of physiological norm and pathology, which can be considered as a compensatory mechanism that supports the function of external respiration.

Amphetamine Stimulates Protein Kinase and Calcium Influx to Increase Corticosterone and Aldosterone Secretion from Male Rat Adrenal Cells

Amphetamine is a potent central nervous system stimulant. Clinical trials have demonstrated that in healthy adults, low (therapeutic) doses of amphetamine can improve i.e., cognition, memory, attention behavior. An amphetamine overdose can affect cardiovascular, central nervous system, musculoskeletal, respiratory, urinary, or sexual function. Furthermore, amphetamine can activate the hypothalamic-pituitary-adrenal axis to increase glucocorticoids and mineralocorticoids released from adrenal. The object of this research was to find out the effect of amphetamine in vivo and in vitro on the production of corticosterone and aldosterone by Zona Fasciculata-Reticularis (ZFR) cells and Zona Glomerulosa (ZG) cells from male rats. For the in vivo study, the rats were given intraperitoneal injections of saline (1 ml/kg/day, group 1), amphetamine (1 mg/ml/kg/day, group 2), or amphetamine (5 mg/ml/kg/day, group 3) for 7 days and then the ZFR or ZG cells from the sacrificed rats were incubated with other drugs. For the in vitro study, the adrenal cells of ZFR or ZG from untreated rats were incubated with amphetamine combined with other drugs. The corticosterone and aldosterone concentrations in samples of the medium were measured using radioimmunoassay. This in vitro and in vivo study illustrated that amphetamine can increase corticosterone secretion by ZFR cells and aldosterone secretion by ZG cells from male rats.

Morin attenuates L-arginine induced acute pancreatitis in rats by downregulating myeloperoxidase and lipid peroxidation

Objective: To explore the therapeutic role of morin against L-arginine-induced acute pancreatitis in rats. Methods: The group 1 received two intraperitoneal injections of normal saline, and groups 2-4 were given two intraperitoneal injections of L-arginine (250 mg/100 g body weight) at 1 h interval to induce acute pancreatitis. Subsequently, group 2 received no further treatment while groups 3 and 4 were treated with morin (30 mg/kg) and diclofenac sodium (30 mg/kg), respectively. Blood glucose and serum levels of insulin, α-amylase, malondialdehyde, myeloperoxidase, alanine aminotransferase, aspartate aminotransferase and cholesterol were measured. Moreover, histopathological study was carried out to investigate the effect of morin treatment on physiology of the pancreas. Results: L-arginine significantly altered the level of blood glucose and serum levels of insulin, α-amylase, malondialdehyde, myeloperoxidase, alanine aminotransferase, aspartate aminotransferase and cholesterol. Treatment with morin or diclofenac sodium significantly improved the levels of these biomarkers. Furthermore, morin showed more significant effect than diclofenac sodium. Histopathological analysis verified that morin protected the pancreas from deleterious effects of L-arginine. Conclusions: Morin plays a protective role against L-arginine- induced acute pancreatitis via reducing lipid peroxidation and tissue inflammation, and attenuating acute pancreatitis-associated alteration in insulin secretion and glucose metabolism.

Влияние ФНО-α, ИЛ-2, ИЛ-5, ИЛ-6 на сокращения мышц трахеи и бронхов крысы

The article discusses the role of TNF-α, IL-2, IL-5, IL-6 in the contractile activity of the smooth muscles of the trachea and bronchi of rats. The studies were carried out on isolated preparations using electrical stimulation of postganglionic nerves (frequency - 30 stim / s, duration - 0.5 ms, amplitude - 20 V, duration of stimulation - 10 s). Two groups of animals were formed: a control group (received an intraperitoneal injection of saline) and an experimental group sensitized with ovalbumin (received an intraperitoneal injection of ovalbumin with its repeated administration after 14 days). Further, the assessment of the contraction of the muscles of the trachea and bronchi after repeated administration of ovalbumin and after perfusion with interleukin solutions was carried out. As a result of the study, it was found that TNF-α, IL-2, IL-5, IL-6 lead to a pronounced increase in the contractile responses of the smooth muscle of the trachea and bronchi both in the control group of animals and in the group of animals sensitized with ovalbumin. The greatest constrictor effect on muscle among the studied cytokines belongs to TNF-α and IL-6.

Ethanol and cyclophosphamide induce similar nephrotoxic effects: possible role for Nox4 and superoxide.

We tested the hypothesis that ethanol consumption would aggravate the renal damage induced by cyclophosphamide (CYP). Male C57BL/6 J mice from control (n= 8) and CYP (n= 12) groups had free access to filtered water and standard rodent chow for 12weeks. Then, 24h before euthanasia mice received an intraperitoneal injection of saline or CYP (300mg/kg). Mice from ethanol (n= 8) and CYP+ ethanol (n= 12) groups had free access to increasing doses of ethanol for 12weeks. Twenty-four hours before euthanasia, mice from ethanol and CYP+ ethanol groups received an intraperitoneal injection of saline or CYP, respectively. Ethanol, CYP, or the association of both drugs augmented serum levels of creatinine and increased the levels of superoxide ([Formula: see text]) generation and thiobarbituric acid reactive substances in the renal cortex. Upregulation of Nox4 and increased activity of superoxide dismutase were detected in the renal cortex of mice treated with ethanol, CYP, or the combination of these drugs; however, these molecular alterations induced by CYP were not potentiated by ethanol consumption. Our findings revealed that chronic ethanol consumption had no potentiating effect on the nephrotoxic effects displayed by CYP. It is possible that the combination of these drugs showed no synergistic effect because they share the same molecular mechanisms of renal toxicity.

Dexmedetomidine inhibits the PSD95-NMDA receptor interaction to promote functional recovery following traumatic brain injury.

The present study examined the effects of dexmedetomidine (Dex) on cognitive and motor recovery in mice following traumatic brain injury (TBI). TBI induces synaptic damage, which leads to motor dysfunction and cognitive decline. Although Dex is known to induce neuroprotection, its role following TBI remains unknown. In the present study, male C57BL/6 mice (8 weeks old; n=72) were subjected to cortical impact injury to generate a TBI mice model. Mice were divided into four groups: TBI, sham, TBI + vehicle, and TBI + Dex. Mice in the TBI + vehicle and TBI + Dex groups received intraperitoneal injections of saline (n=18) and 100 µg/kg Dex (n=18), respectively, at 1 and 12 h following surgery. At 24 h post-injury, 10 animals from each group were sacrificed, and brain tissue was isolated for Fluoro-Jade B staining and RNA and protein extraction. At 72 h post-TBI, motor function was evaluated. Furthermore, cognitive impairment was assessed between day 14 and 19 using the Morris water maze. The results demonstrated that the mRNA and protein expression of post-synaptic density 95 (PSD95) was reduced post-TBI. In addition, neuronal degeneration was evaluated using FJB staining, where PSD95 formed a complex with the N-methyl-D-aspartic acid (NMDA) receptor subunit (NR2B) and neuronal nitric oxide synthase (nNOS) inducing neuronal death post-TBI. Treatment with Dex efficiently decreased the PSD95-NR2B-nNOS interaction, which reduced the TBI-induced neuronal death. Furthermore, Dex treatment contributed to the enhanced cognitive and motor recovery following TBI. The results from the present study reported a potential mechanistic action of Dex treatment post-TBI, which may be associated with the inhibition of PSD95-NMDA interaction.

Investigation of regulation and mechanism of miR-223 on autophagy of CD4 + T lymphocytes in septic mice

T-lymphocyte dysfunction is most important part of immune dysfunction in sepsis, where dynamic change, especially autophagy of CD4+T lymphocytes is found to be related to disease fate. Our study is to i nvestigate the changes of CD4 + T lymphocytes and their autophagy levels in septic miR-223 −/− mouse model injected intraperitoneally with E. coli.120 male C57BL/6J wild-type. Twenty male miR-223 knockout(miR-223-/-) mice were randomly divided into, according to intraperitoneal injection of normal saline (NS) and E. coli solution, normal saline (WT NS) group, sepsis (WT Sep) group, miR-223 −/− NS group and miR-223 −/− Sep group, respectively. The autophagy related protein was monitored with flow cytometry to observe the autophagy of CD4+T lymphocytes. Flow cytometry showed the proportion of CD4 + T lymphocytes in peripheral blood circulation, alveoli, and spleen of mice in the WT Sep group gradually decreased after surgery, the proportion of cells with autophagic activity in this population of cells was significantly higher than that in the WT NS group, and the proportion of CD4 + T lymphocytes with active autophagic activity in miR-223 −/− mice were significantly decreased, but higher than that in the miR-223 −/− NS group and lower than the level of autophagy in CD4 + T cells of wild-type mice. Thus, miR-223 can up-regulate the level of autophagy in CD4 + T lymphocytes of septic mice, suggesting that miR-223 may be used as a potential target for the prevention and treatment of sepsis.

Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory

Inhibition of the angiotensin type 1 receptor (AT1R) has been shown to decrease fear responses in both humans and rodents. These effects are attributed to modulation of extinction learning, however the contribution of AT1R to alternative memory processes remains unclear. Using classic Pavlovian conditioning combined with radiotelemetry and whole-genome RNA sequencing, we evaluated the effects of the AT1R antagonist losartan on fear memory reconsolidation. Following the retrieval of conditioned auditory fear memory, animals were given a single intraperitoneal injection of losartan or saline. In response to the conditioned stimulus (CS), losartan-treated animals exhibited significantly less freezing at 24 h and 1 week; an effect that was dependent upon memory reactivation and independent of conditioned cardiovascular reactivity. Using an unbiased whole-genome RNA sequencing approach, transcriptomic analysis of the basolateral amygdala (BLA) identified losartan-dependent differences in gene expression during the reconsolidation phase. These findings demonstrate that post-retrieval losartan modifies behavioral and transcriptomic markers of conditioned fear memory, supporting an important regulatory role for this receptor in reconsolidation and as a potential pharmacotherapeutic target for maladaptive fear disorders such as PTSD.

Novel mechanism of action for the mood stabilizer lithium

Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein-1 (AP-1) inhibitor for 24-72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT-qPCR. In vitro studies showed lithium-treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP-1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium-treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP-1 transcription factor.