Chia seeds oil ameliorate chronic immobilization stress-induced neurodisturbance in rat brains via activation of the antioxidant/anti-inflammatory/antiapoptotic signaling pathways.

Chronic immobilization stress plays a key role in several neuropsychiatric disorders. This investigation assessed the possible ameliorative effect of chia seed oil (CSO) against the neurodisturbance-induced in rats by chronic immobilization. Rats were randomly allocated into control, CSO (1 ml/kg b.wt./orally), restrained (6 h/day), CSO pre-restraint, and CSO post-restraint for 60 days. Results revealed a significant reduction in serum corticosterone level, gene expression of corticotrophin-releasing factor, pro-inflammatory cytokines, and oxidative biomarkers in restrained rats treated with CSO. The histopathological findings revealed restoring necrosis and neuronal loss in CSO-treated-restraint rats. The immunohistochemical evaluation revealed a significant reduction in the immuno-expression of caspase-3, nuclear factor kappa B, interleukin-6, and cyclooxygenase-2 (COX-2), and an elevation of calbindin-28k and synaptophysin expression compared to non-treated restraint rats. The molecular docking showed the CSO high affinity for several target proteins, including caspase-3, COX-2, corticotropin-releasing hormone binding protein, corticotropin-releasing factor receptors 1 and 2, interleukin-1 receptor types 1 and 2, interleukin-6 receptor subunits alpha and beta. In conclusion, CSO emerges as a promising candidate against stress-induced brain disruptions by suppressing inflammatory/oxidative/apoptotic signaling pathways due to its numerous antioxidant and anti-inflammatory components, mainly α-linolenic acid. Future studies are necessary to evaluate the CSO therapeutic impacts in human neurodisturbances.

Monoterpenoids from the root bark of Acanthopanax gracilistylus and their inhibitory effects on neutrophil elastase, 5-lipoxygenase, andcyclooxygenase-2 in vitro.

Twenty-four monoterpenoids, including three previously undescribed compounds (1-3), were isolated from the root bark of Acanthopanax gracilistylus W. W. Smith (Acanthopanacis Cortex). Their structures were unambiguously established based on spectroscopic analysis (HR-ESIMS, IR, 1D, and 2D NMR), and the absolute configurations of 1-3 were elucidated by comparing their experimental and calculated electronic circular dichroism spectra. In addition, the structure of 8 was confirmed by single-crystal X-ray diffraction. The inhibitory activities of 1-24 against neutrophil elastase, 5-lipoxygenase, and cyclooxygenase-2 (COX-2) were studied in vitro for the first time, and the results showed that compound 24 possessed a significant inhibitory effect on COX-2 with an IC50 value of 1.53 ± 0.10 µΜ. This research first reported the presence of monoterpenoids in Acanthopanacis Cortex, including one monoterpenoid 2 with an unusual 4/5 bicyclic lactone system, and compounds 4 and 5 have never been reported in nature.

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV.

Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined. Likewise, the necessity for human cells to encode two Tim8 proteins and whether any potential redundancy exists is unclear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we define the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8-deficient cells have a COX2 and COX3 module defect and exhibit an accumulation of the Complex IV S2 subcomplex. These data suggest that hTim8a and hTim8b function in assembly of Complex IV via interactions with intermediate-assembly subcomplexes. We propose that hTim8-hTim13 complexes are auxiliary assembly factors involved in the formation of the Complex IV S3 subcomplex during assembly of mature Complex IV.

Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages.

Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane-enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP-induced macrophage activation. Indeed, pEV-treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro-inflammatory IL-6 and TNF-α and increased IL-10 response. This anti-inflammatory activity was associated with the promotion of tissue-repair functions in macrophages, characterized by augmented efferocytosis and pro-angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti-inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV-mediated induction of COX2 is critical for the pEV-mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M-CSF-induced differentiation to macrophages increased efferocytosis and diminished pro-inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions.

Ferocactus herrerae Fruits: Nutritional Significance, Phytochemical Profiling, and Biological Potentials.

The current study reports for the first time the nutritional, fruit volatiles, phytochemical, and biological characteristics of Ferocactus herrerae J. G. Ortega fruits. The nutritional analysis revealed that carbohydrate (20.6%) was the most abundant nutrient followed by dietary fibers (11.8%), lipids (0.9%), and proteins (0.8%). It was rich in vitamins, minerals, essential, and non-essential amino acids. Gas chromatography-mass spectrometry (GC-MS) analysis of the headspace-extracted volatiles showed that 3-methyl octadecane (35.72 ± 2.38%) was the major constituent detected. Spectrophotometric determination of total phenolic and flavonoid contents of the fruit methanolic extract (ME) showed high total phenolic [9.17 ± 0.87 mg/g gallic acid equivalent (GAE)] and flavonoid [4.99 ± 0.23 mg/g quercetin equivalent (QE)] contents. The ME was analyzed using high-performance liquid chromatography with ultraviolet (HPLC-UV), which allowed for both qualitative and quantitative estimation of 16 phenolic compounds. Caffeic acid was the major phenolic acid identified [45.03 ± 0.45 mg/100 g dried powdered fruits (DW)] while quercitrin (52.65 ± 0.31 mg/100 g DW), was the major flavonoid detected. In-vitro assessment of the antioxidant capacities of the ME revealed pronounced activity using three comparative methods; 2, 2-diphenyl-1-picrylhydrazyl (DPPH) (132.06 ± 2.1 µM Trolox equivalent (TE) /g), 2,2'-azino-di(3-ethylbenzthiazoline-6-sulfonic acid (ABTS), (241.1 ± 5.03 uM TE/g), and ferric reducing antioxidant power (FRAP) (258.9 ± 1.75 uM TE/g). Besides, remarkable anti-inflammatory [COX-1 (IC50 = 20.2 ± 1.1 µg/mL) and COX-2 (IC50 = 9.8 ± 0.64 µg/mL)] and acetylcholinesterase inhibitory (IC50 = 1.01 ± 0.39 mg/mL) activities were observed. Finally, our results revealed that these fruits could be used effectively as functional foods and nutraceuticals suggesting an increase in their propagation.

Salivary GFAP as a potential biomarker for diagnosis of mild cognitive impairment and Alzheimer's disease and its correlation with neuroinflammation and apoptosis.

Glial fibrillary acidic protein (GFAP) is the main constituent of the astrocytic cytoskeleton, overexpressed during reactive astrogliosis-a hallmark of Alzheimer's Disease (AD). GFAP and established biomarkers of neurodegeneration, inflammation, and apoptosis have been determined in the saliva of amnestic-single-domain Mild Cognitive Impairment (MCI) (Ν = 20), AD (Ν = 20) patients, and cognitively healthy Controls (Ν = 20). Salivary GFAP levels were found significantly decreased in MCI and AD patients and were proven an excellent biomarker for discriminating Controls from MCI or AD patients. GFAP levels correlate with studied biomarkers and Aß42, IL-1ß, and caspase-8 are its main predictors.

The Upregulation of COX2 in Human Degenerated Nucleus Pulposus: The Association of Inflammation with Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is an important risk factor of low back pain. We previously found upregulated markers of fibrosis, the late stage of chronic inflammation, in degenerated IVD with a small number of clinical specimens. Here, we aimed to study on a larger scale the association of cyclooxygenase 2 (COX2), an inflammation and/or pain marker, with IVDD. This study involved 107 LBP participants. The IVD degeneration level was graded on a 1-5 scale according to the Pfirrmann classification system. Discs at grades 1-3 were further grouped as white discs with grades 4-5 as black discs. We recorded baseline information about age, gender, body mass index (BMI), diabetes history, smoking history, and magnetic resonance imaging (MRI). Their association with IVDD was statistically analyzed. The expression level of COX2 was investigated by immunohistochemistry. The total integrated COX2 optical density (IOD), number of COX2-positive cells, and total cell number of each image were counted and analyzed by Image-Pro Plus software. The IOD and number of COX2-positive cells were divided by the total cell number to obtain COX2 expression density (IOD/cell) and COX2 positivity (cell+/cell). As a result, among the baseline information investigated, only age was found to have a significant association with IVDD. The IOD/cell was found to be significantly increased from grade 2 to grade 5, as well as in black discs compared to white discs. The cell+/cell displayed the same trend that it increased in highly degenerative discs compared to their counterparts. In conclusion, the expression of COX2 is associated with IVDD, which highlights COX2 as a biomarker for IVD degeneration and indicates the involvement of inflammation and pain signaling in IVDD.

Anti-inflammatory effect of Adelia ricinella L. aerial parts.

OBJECTIVE: To investigate the main chemical components and the anti-inflammatory activity of extracts of Adelia ricinella L. aerial parts. METHODS: Three extracts obtained by soxhlet extraction and ethanol/water mixtures were evaluated in their chemical composition by UPLC-DAD-MS/MS. The in vitro anti-inflammatory activity of the prepared extracts was assessed through three different assays: COX-1 and COX-2 enzymatic inhibition, cell-based COX assays on RAW264.7 macrophages (ATCC) measuring the COX-2 protein expression by Western blot and the measurement of the PGE2 concentration in the supernatants of the culture medium. Also was determinate the effect of the three extracts on the RAW 264.7 cell viability. KEY FINDINGS: Few differences in the phytochemical profile were found between the three prepared extracts, identifying a blend of thirteen flavonoids derived from luteolin and apigenin, with orientin as main constituent. Plant extracts (alcoholic and aqueous) did not affect the macrophage cell viability (IC50 > 256 µg/ml) and significantly reduced COX-1 and COX-2 enzyme activities. Additionally, COX-2 expression and PGE2 release were suppressed after 24 h of LPS stimulation and treatment with plant extracts (8-64 µg/ml). CONCLUSIONS: A. ricinella extracts showed the ability to reduce the inflammatory effect exerted by LPS in murine macrophages. However, further studies should confirm their anti-inflammatory activity.

Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

Pro-inflammatory mediators and signaling proteins in the decidua of pre-eclampsia.

OBJECTIVE: To evaluate the role of CD68+ macrophages and inflammatory/signaling proteins in the decidua of singleton pregnancies with late-onset pre-eclampsia. PATIENTS AND METHODS: This study was designed as a prospective case-control study. Decidual tissue samples were obtained from twenty healthy pregnant women as a control group and twenty pregnant women with late-onset pre-eclampsia showing severe symptoms as the study group. We examined the abundance of CD68+ macrophages in both groups using flow cytometry. Protein and mRNA expression levels of inflammatory/signaling proteins, including inducible nitric oxide synthase, nuclear factor-κB inhibitor α, cyclooxygenase-2, and phosphorylated c-Jun N-terminal kinase, in the decidua of both groups were measured using Western blotting and Reverse Transcription-Polymerase Chain Reaction, respectively. Student's t-tests were performed for statistical analysis. RESULTS: The numbers of CD68+ macrophages were similar in the study and control groups (p=0.47). However, the levels of inducible nitric oxide synthase, nuclear factor-κB, cyclooxygenase-2, and phosphorylated c-Jun N-terminal kinase were significantly increased in the study group. Therefore, pro-inflammatory mediators and signaling proteins in the decidua during pre-eclampsia may be related to the pathogenesis of pre-eclampsia. CONCLUSIONS: Pre-eclampsia-induced alterations in the expression of inflammatory/signaling proteins in the decidua during singleton pregnancies may play a critical role in the pathogenesis of pre-eclampsia.

Comparative expression of cyclooxygenase 2 and Ki67 in amelanotic and conventional oral melanomas

BACKGROUND: Oral melanomas have some histopathological resemblance with its cutaneous counterpart; howev-er, an aggressive behavior is more common in tumors that occur in the oral cavity. Several markers have been suggested as indicative of tumoral progression and aggressiveness, such as cyclooxygenase 2 (COX-2) and Ki67. MATERIAL AND METHODS: In this study, we have compared the expression of COX-2 and Ki67 in a series of amelanotic (n = 7) and melanotic oral melanomas (n = 22). The cases were selected from 4 pathology laboratories and sub-mitted to the immunohistochemical (IHC) reactions. We analyzed the IHC staining based on a qualitative - using visual scores; and a computer-assisted method (quantitative) using scanned slides and software for digital analysis. RESULTS: COX-2 was expressed in all oral melanomas; however, its intensity was significantly higher in the amelanotic ones (P < 0.001). Similarly, a high Ki67-positivity index was observed in the amelanotic than melanotic ones (P < 0.001). CONCLUSIONS: Based on these results, we suggest that amelanotic oral melanomas have marked pro-inflammatory and high-proliferative phenotype, justifying their more aggressive behavior compared with the melanotic ones

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Hippocampal Cholinergic Neurostimulating Peptide Suppresses LPS-Induced Expression of Inflammatory Enzymes in Human Macrophages.

Hippocampal cholinergic neurostimulating peptide (HCNP) is a secreted undecapeptide produced through proteolytic cleavage of its precursor protein, HCNPpp. Within hippocampal neurons, HCNP increases gene expression of choline acetyltransferase (ChAT), which catalyzes acetylcholine (ACh) synthesis, thereby modulating neural activity. HCNPpp also appears to be expressed in various immune cells. In the present study, we observed that HCNPpp is expressed in U937 human macrophage-like cells and that HCNP exposure suppresses lipopolysaccharide (LPS)-induced gene expression of ChAT. The opposite action is also seen in T lymphocytes, which suggest that HCNP appear to suppress cholinergic system in immune cells. In addition, HCNP suppresses LPS-induced gene expression of inflammatory enzymes including cyclooxygenase 2 (COX2) and inducible nitric oxide (NO) synthase (iNOS). The suppressive effect of HCNP may reflect suppression of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling activated by LPS. Thus, HCNP may have therapeutic potential as an anti-inflammatory drug.

Root canal contamination or exposure to lipopolysaccharide differentially modulate prostaglandin E 2 and leukotriene B 4 signaling in apical periodontitis.

Purpose To evaluate the kinetics of apical periodontitis development in vivo , induced either by contamination of the root canals by microorganisms from the oral cavity or by inoculation of bacterial lipopolysaccharide (LPS) and the regulation of major enzymes and receptors involved in the arachidonic acid metabolism. Methodology Apical periodontitis was induced in C57BL6 mice (n=96), by root canal exposure to oral cavity (n=48 teeth) or inoculation of LPS (10 µL of a suspension of 0.1 µg/µL) from E. coli into the root canals (n= 48 teeth). Healthy teeth were used as control (n=48 teeth). After 7, 14, 21 and 28 days the animals were euthanized and tissues removed for histopathological and qRT-PCR analyses. Histological analysis data were analyzed using two-way ANOVA followed by Sidak's test, and qRT-PCR data using two-way ANOVA followed by Tukey's test (α=0.05). Results Contamination by microorganisms led to the development of apical periodontitis, characterized by the recruitment of inflammatory cells and bone tissue resorption, whereas inoculation of LPS induced inflammatory cells recruitment without bone resorption. Both stimuli induced mRNA expression for cyclooxygenase-2 and 5-lipoxygenase enzymes. Expression of prostaglandin E 2 and leukotriene B 4 cell surface receptors were more stimulated by LPS. Regarding nuclear peroxisome proliferator-activated receptors (PPAR), oral contamination induced the synthesis of mRNA for PPARδ, differently from inoculation of LPS, that induced PPARα and PPARγ expression. Conclusions Contamination of the root canals by microorganisms from oral cavity induced the development of apical periodontitis differently than by inoculation with LPS, characterized by less bone loss than the first model. Regardless of the model used, it was found a local increase in the synthesis of mRNA for the enzymes 5-lipoxygenase and cyclooxygenase-2 of the arachidonic acid metabolism, as well as in the surface and nuclear receptors for the lipid mediators prostaglandin E2 and leukotriene B4.

PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study.

BACKGROUND: Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. METHODS: The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. RESULTS: COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BPND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BPND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. CONCLUSIONS: Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03912428. Registered April 11, 2019.

Longitudinal Changes of NF-κB Downstream Mediators and Peritoneal Transport Characteristics in Incident Peritoneal Dialysis Patients.

The role of intra-peritoneal mediators in the regulation peritoneal transport is not completely understood. We investigate the relation between longitudinal changes in dialysis effluent level of nuclear factor kappa-B (NF-κB) downstream mediators and the change in peritoneal transport over 1 year. We studied 46 incident PD patients. Their peritoneal transport characteristics were determined after starting PD and then one year later. Concomitant dialysis effluent levels of interleukin-6 (IL-6), cyclo-oxygenase-2 (COX-2) and hepatocyte growth factor (HGF) are determined. There were significant correlations between baseline and one-year dialysis effluent IL-6 and COX-2 levels with the corresponding dialysate-to-plasma creatinine level at 4 hours (D/P4) and mass transfer area coefficient of creatinine (MTAC). After one year, patients who had peritonitis had higher dialysis effluent IL-6 (26.6 ± 17.4 vs 15.1 ± 12.3 pg/ml, p = 0.037) and COX-2 levels (4.97 ± 6.25 vs 1.60 ± 1.53 ng/ml, p = 0.007) than those without peritonitis, and the number of peritonitis episode significantly correlated with the IL-6 and COX-2 levels after one year. In contrast, dialysis effluent HGF level did not correlate with peritoneal transport. There was no difference in any mediator level between patients receiving conventional and low glucose degradation product solutions. Dialysis effluent IL-6 and COX-2 levels correlate with the concomitant D/P4 and MTAC of creatinine. IL-6 and COX-2 may contribute to the short-term regulation of peritoneal transport.

COX-2 as a potential biomarker and therapeutic target in melanoma.

With a constantly increasing incidence, cutaneous melanoma has raised the need for a better understanding of its complex microenvironment that may further guide therapeutic options. Melanoma is a model tumor in immuno-oncology. Inflammation represents an important hallmark of cancer capable of inducing and sustaining tumor development. The inflammatory process also orchestrates the adaptative immunosuppression of tumor cells that helps them to evade immune destruction. Besides its role in proliferation, angiogenesis, and apoptosis, cyclooxygenase-2 (COX-2) is a well-known promoter of immune suppression in melanoma. COX-2 inhibitors are closely involved in this condition. This review attempts to answer two controversial questions: is COX-2 a valuable prognostic factor? Among all COX-2 inhibitors, is celecoxib a suitable adjuvant in melanoma therapy?

Ganoderma cochlear Metabolites as Probes to Identify a COX-2 Active Site and as in Vitro and in Vivo Anti-Inflammatory Agents.

(±)-Dispirocochlearoids A-C (1-3), meroterpenoids with a 6/6/5/6/6/6 ring system, were isolated from Ganoderma cochlear. 1-3 are selective COX-2 inhibitors with an IC50 value of (-)-2 at 386 nM. Site-directed mutagenesis identified His351 as a COX-2 active site. In vivo anti-inflammatory activities of (-)-2 were performed against acute lung injury in mice.

4-Hydroxycinnamic acid suppresses airway inflammation and mucus hypersecretion in allergic asthma induced by ovalbumin challenge.

In this study, we investigated whether 4-hydroxycinnamic acid (HA) has a palliative effect on asthmatic inflammatory responses using a mouse model of ovalbumin (OVA)-induced allergic asthma. The mice were divided into five groups, each consisting of seven females (normal control phosphate-buffered saline); OVA (OVA sensitization/challenge); dexamethasone (DEX, OVA sensitization/challenge + dexamethasone 3 mg/kg); HA-10 and HA-20 OVA sensitization/challenge + HA 10 and 20 mg/kg, respectively). Mice treated with HA showed a reduction in airway hyperresponsiveness and in the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) compared with asthmatic control. HA treatment also reduced the levels of interleukin (IL)-5 and IL-13 in BALF and of OVA-specific immunoglobulin E in the serum compared with asthmatic control. HA treatment relieved airway inflammation and mucus overproduction caused by OVA exposure. Additionally, HA inhibited the increases in levels of nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2 that normally occur after OVA exposure. HA treatment also reduced the activity and protein level of matrix metalloproteinase-9. Taken together, HA effectively suppressed asthmatic airway inflammation and mucus production caused by OVA exposure. These findings indicate that HA has the potential to be used as a therapeutic agent for asthma.

Protective Effects of Polysaccharide Extracted from Portulacae oleracea L. on Colitis Induced by Dextran Sulfate Sodium.

Polysaccharide from Ma-chi-xian (Portulacae oleracea L., POLP) was prepared and the therapeutic effect on dextran sodium sulfate-induced colitis mice was investigated in this study. The results of clinical activity score and H&E staining confirmed the therapeutic effect of POLP. POLP could diminished the symptoms of colitis and improve colon histopathological structure of the colitis mice. The expression levels of four cytokines were determined. The concentrations of PGE2 and IL-6 were downregulated by POLP treatment. The COX-2 protein expression levels and the STAT3 phosphorylation levels were detected. The results showed that these two protein levels were all increased in colitis and decreased after POLP treatment, indicating that these two proteins were closely related with the protective effect of POLP. Because the synthesis of PGE2 is catalyzed by COX-2 and phosphorylation of STAT3 can induce the expression of COX-2, it was concluded that STAT3 was a key protein related to the POLP exerting its activity in colitis.

Root canal contamination or exposure to lipopolysaccharide differentially modulate prostaglandin E 2 and leukotriene B 4 signaling in apical periodontitis

Abstract Purpose To evaluate the kinetics of apical periodontitis development in vivo , induced either by contamination of the root canals by microorganisms from the oral cavity or by inoculation of bacterial lipopolysaccharide (LPS) and the regulation of major enzymes and receptors involved in the arachidonic acid metabolism. Methodology Apical periodontitis was induced in C57BL6 mice (n=96), by root canal exposure to oral cavity (n=48 teeth) or inoculation of LPS (10 µL of a suspension of 0.1 µg/µL) from E. coli into the root canals (n= 48 teeth). Healthy teeth were used as control (n=48 teeth). After 7, 14, 21 and 28 days the animals were euthanized and tissues removed for histopathological and qRT-PCR analyses. Histological analysis data were analyzed using two-way ANOVA followed by Sidak's test, and qRT-PCR data using two-way ANOVA followed by Tukey's test (α=0.05). Results Contamination by microorganisms led to the development of apical periodontitis, characterized by the recruitment of inflammatory cells and bone tissue resorption, whereas inoculation of LPS induced inflammatory cells recruitment without bone resorption. Both stimuli induced mRNA expression for cyclooxygenase-2 and 5-lipoxygenase enzymes. Expression of prostaglandin E 2 and leukotriene B 4 cell surface receptors were more stimulated by LPS. Regarding nuclear peroxisome proliferator-activated receptors (PPAR), oral contamination induced the synthesis of mRNA for PPARδ, differently from inoculation of LPS, that induced PPARα and PPARγ expression. Conclusions Contamination of the root canals by microorganisms from oral cavity induced the development of apical periodontitis differently than by inoculation with LPS, characterized by less bone loss than the first model. Regardless of the model used, it was found a local increase in the synthesis of mRNA for the enzymes 5-lipoxygenase and cyclooxygenase-2 of the arachidonic acid metabolism, as well as in the surface and nuclear receptors for the lipid mediators prostaglandin E2 and leukotriene B4.