Release Of Chemical Mediators Research Articles

Effect of Polyphenols in Sea Buckthorn Berry on Chemical Mediator Release from Mast Cells.

Sea buckthorn (Hippophae rhamnoides L.) is a deciduous shrub of the Elaeagnaceae family and is widely distributed in northern Eurasia. Sea buckthorn berry (SBB) has attracted attention for its use in many health foods, although its physiological function remains unknown. In this study, we investigated the inhibitory effect of SBB extract and its fractions on Type-I allergy using mast cell lines. Among these fractions, SBB fraction with the highest amount of antioxidant polyphenols significantly inhibited the release of chemical mediators such as histamine and leukotriene B4 (LTB4) from the stimulated mast cells. This fraction also inhibited the influx of calcium ions (Ca2+) and the phosphorylation of tyrosine residues in proteins, including spleen tyrosine kinase, which is associated with signal transduction during the release of chemical mediators. The active SBB fraction contained isorhamnetin as its major flavonol aglycon. Isorhamnetin inhibited histamine and LTB4 release from the stimulated cells and suppressed intracellular Ca2+ influx. These results indicate that isorhamnetin is the primary substance responsible for the antiallergic activity in SBB. In conclusion, SBB may alleviate Type-I allergy by inhibiting the release of chemical mediators from mast cells, and polyphenols may contribute to this effect.

Pathophysiology and treatment of pain in multiple myeloma

Most patients with multiple myeloma (MM) suffer from chronic pain of varying degrees of intensity at every stage of the natural disease process. Osteolytic bone lesions are one of the most common complications of MM. The bone disease visualized by PET/CT and MRI affects up to 90% of newly diagnosed MM patients, increasing the risk of the development of skeletal-related events. Pathological fractures and spinal cord compression occur in 17% and 6% of patients, respectively. Bone pain is explained by an increase in pressure in the bone marrow, the release of chemical mediators by myeloma plasma cells, and the occurrence of microcracks in the bones, indirectly to a violation of local metabolism. Management of myeloma bone disease includes anti-myeloma chemotherapy and radiotherapy, antiresorptive therapy with bisphosphonates or denosumab, and direct pharmacological pain correction. Patients with pathological vertebral fractures and without spinal cord compression should be considered for vertebroplasty or kyphoplasty. The use of proteasome inhibitors and monoclonal antibodies for the treatment of MM is associated with a risk of herpes simplex virus (HSV) and varicella-zoster virus (VZV) reactivation. The result of the healing of herpetic eruptions in some patients will be the development of postherpetic neuralgia, manifested by excruciating pain for months or years. Moreover, the treatment with proteasome inhibitor bortezomib is often associated with the development of long-term persistent peripheral neuropathy, often complicated by pain. According to their neurobiological and clinical features, pain is classified into nociceptive, neuropathic, and functional. Bone pain is nociceptive and for postherpetic and chemotherapy-induced neuropathy, the neuropathic component is more significant. Opioids are the drugs of choice for moderate to severe nociceptive pain, while anticonvulsants and antidepressants are the most commonly used adjuvants for neuropathic pain. This review summarizes information on the pathophysiology of various types of pain syndrome in patients with MM, as well as on modern approaches to the prevention and treatment of complications. The issues of the pharmacology of opioid analgesics are discussed. The review concludes with data from a clinical trial of a new domestic non-opioid μ1-opioid receptor agonist Tafalgin, considered a real alternative to narcotic analgesics.

The complement system in preeclampsia: a review of its activation and endothelial injury in the triad of COVID-19 infection and HIV-associated preeclampsia.

This review assesses the complement system and its activation, with the pathological features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human immunodeficiency virus (HIV) infection and preeclampsia (PE). The complement system is the first defensive response by the host innate immune system to viral pathogens, including SARS-CoV-2. SARS-CoV-2 entry results in the release of pro-inflammatory cytokines and chemical mediators to create a "cytokine storm". Endothelial cell (EC) dysfunction and cell-mediated injury are also present. These factors cause an exacerbated inflammatory state. During HIV infection and PE, various complement components are elevated, causing a hyper-inflammatory state. Furthermore, EC dysfunction and cell-mediated injury are also present. The similarities in pathological aspects of these three disorders may emanate from excessive complement activation. This review serves as a platform for further research on the complement system, coronavirus disease 2019, HIV infection and PE.

Evaluation of oral cancer-induced chemosensitivity

<h3>Introduction</h3> Oral cancer patients experience severe function related pain that impacts quality of life. Some patients report sensitivity to spicy food. Pain is attributed to neuronal sensitization by the release of chemical mediators from the cancer and cancer microenvironment that activate TRPV1 (transient receptor potential cation channel subfamily V member 1). To better understand the underlying mechanisms of oral cancer pain, this study was designed to evaluate cancer-induced chemosensitivity in oral cancer preclinical models. <h3>Materials and Methods</h3> A two-bottle preference test was used to measure aversion to the TRPV1 agonist, capsaicin, the spicy compound in chili peppers. Naïve wild type mice (C57BL/6) were housed two to five mice per cage. Liquid intake over 5-7 day periods was measured from two drinking bottles one with water and capsaicin (0.25 µM – 1 µM) and the other vehicle (0.1% ethanol). Positions of the bottles were exchanged daily to avoid habituation. <h3>Results</h3> Female C57BL/6 mice drank less water with capsaicin for all tested concentrations of capsaicin, demonstrating aversion. Male C57BL/6 mice demonstrated aversion to capsaicin concentrations greater than 0.25 µM. Aversion increased in successive trials, suggesting conditioning or sensitization. Male mice that did not show aversion to 0.25 µM capsaicin over three successive trials demonstrated aversion to 0.25 µM capsaicin after injection in the tongue with complete Freund's adjuvant (20 µl) to generate inflammatory pain. <h3>Conclusions</h3> Female mice showed greater sensitivity to capsaicin than male mice. Aversion to a non-aversive concentration of capsaicin was demonstrated in male mice with inflammatory pain. The lowest dose of capsaicin is expected identify the change in chemosensitivity and difference between sensitive vs. non sensitive cancers.

Biochemical and Haematological Manifestations as Predictor for Covid-19: A Case-Control Study

Background: Corona virus causes severe pneumonia of idiopathic nature. The clinical manifestation ranges from mild to severe respiratory problems. Due presences of target receptors and the release of chemical mediators, it also affect other organs including the liver and kidney. Objective: The purpose of this study was to determine the effect of COVID-19 infection on hematological parameters, liver function and renal function. Methods: This multicenter case-control observational study was conducted at Lady reading hospital, Hayatabad medical complex and Khyber teaching hospital Peshawar. A total of 340 samples were processed including 170 COVID-19 patients and 170 control groups. Complete blood count, liver function tests and renal function tests were performed to determine the effect of COVID infection on these parameters. The data were statistically analyzed using SPSS version 22.0. Results: In complete blood count, the mean WBC count was 16632.34±7339.94 which was statistically significant with p value less than 0.05. In differential leukocyte count, the mean neutrophil values were 87.79±7.36 which was statistically significant (p=0.00). The mean value of ALT and ALP were 49.47±100.08, 114.43±64.71 respectively which were higher than the control group. Mean value of urea and creatinine were 70.58±41.89, 1.31±1.12 respectively and was statistically significant (p=0.00). Conclusion: it is concluded that COVID-19 infection affects hematological and biochemical parameters including ALT, ALP, urea and creatinine. Hence these manifestations can be used collectively as a diagnostic and prognostic biomarker. Keywords: Covid-19, liver function tests, Kidney Function Tests, blood cell count

Biochemical and Haematological Manifestations as Predictor for Covid-19: A Case-Control Study

Background: Corona virus causes severe pneumonia of idiopathic nature. The clinical manifestation ranges from mild to severe respiratory problems. Due presences of target receptors and the release of chemical mediators, it also affect other organs including the liver and kidney. Objective: The purpose of this study was to determine the effect of COVID-19 infection on hematological parameters, liver function and renal function. Methods: This multicenter case-control observational study was conducted at Lady reading hospital, Hayatabad medical complex and Khyber teaching hospital Peshawar. A total of 340 samples were processed including 170 COVID-19 patients and 170 control groups. Complete blood count, liver function tests and renal function tests were performed to determine the effect of COVID infection on these parameters. The data were statistically analyzed using SPSS version 22.0. Results: In complete blood count, the mean WBC count was 16632.34±7339.94 which was statistically significant with p value less than 0.05. In differential leukocyte count, the mean neutrophil values were 87.79±7.36 which was statistically significant (p=0.00). The mean value of ALT and ALP were 49.47±100.08, 114.43±64.71 respectively which were higher than the control group. Mean value of urea and creatinine were 70.58±41.89, 1.31±1.12 respectively and was statistically significant (p=0.00). Conclusion: it is concluded that COVID-19 infection affects hematological and biochemical parameters including ALT, ALP, urea and creatinine. Hence these manifestations can be used collectively as a diagnostic and prognostic biomarker. Keywords: Covid-19, liver function tests, Kidney Function Tests, blood cell count

Feline cutaneous atopic syndrome: Case Report

Atopic dermatitis (AD) is an inflammatory, itchy and chronic disease and is characterized by a predisposition to develop signs of hypersensitivity after repeated exposure to allergens that in most cases are aeroallergens (pollen and mites). Its development is related to the interaction between genetic and environmental factors that promote changes in the skin barrier. This facilitates the transepidermal penetration of allergens, which come into contact with immune cells present in the skin, triggering an immune response by Th2 lymphocytes. These, in turn, stimulate a high production of IgE, which activates mast cells, stimulating the release of chemical mediators, culminating in the inflammatory process characteristic of AD. In this case, a 7-year-old castrated, spayed female cat weighing 3,900 kg was seen. The animal had intense itching and skin lesions since the age of 1.5 years, which were responsive to the steroid, but when weaning was performed, the lesions returned. On physical examination, the animal presented plaque lesions in the abdominal and axillary region and abrasions in the left ear. The animal was initially treated with cyclosporine and prednisolone, which showed good improvement of the symptoms presented, but had some side effects such as diarrhea, sneezing and nasal and ocular secretion and gingival hyperplasia, which were treated with Fanciclovir and azithromycin-based paste. The animal improved its symptoms after the treatment and even after weaning from cyclosporine it remained well and with a good response to the treatment

Biological Principles of Orthodontic Tooth Movement: A Review Article

Orthodontic tooth mobility is discussed in this article, and the numerous concepts or theories of movement of tooth and the phases through which a tooth undergoes after application of forces. The effect of orthodontic pressure exerted on the dental architecture promotes movement of tooth through remodeling, which is the growth and resorption of alveolar bone. These forces can either be light forces or heavy forces depending upon their magnitudes. Biological aspects of tooth movement changes in accordance with the magnitude, force, time span and direction of force exerted. Variations in force application can be decided based on the kind of movement of tooth desired. These forces result in complex physiological events, cellular events in the surrounding tissues and, release of various chemical mediators to re-establish the equilibrium which gets interrupted by applying forces. &#x0D; Recently, many researches are going on how to enhance the speed of movement of the tooth with light forces so as to reduce the damage caused by the heavy forces, reduce the treatment time overall and treatment planning which results in minimal adverse effects.

IL-10 in Mast Cell-Mediated Immune Responses: Anti-Inflammatory and Proinflammatory Roles.

Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10.

Dieckol isolated from a brown alga, Eisenia nipponica, suppresses ear swelling from allergic inflammation in mouse.

We previously found a lipophilic fraction of the methanol/chloroform extract of a brown alga, Eisenia nipponica, that had an antiallergic effect in a murine ear swelling test. In this study, we purified the active component from the lipophilic fraction using high performance liquid chromatography and analyzed the mass and nuclear magnetic resonance spectra. This uncovered the phlorotannin dieckol, which exhibited antiallergic effects in an ear swelling test using mice sensitized by arachidonic acid, 12-O-tetradecanoylphorbol-13-acetate, and oxazolone. Mechanistic investigations indicated that dieckol suppressed degranulation, chemical mediator release, and the expression of mRNA such as cyclooxygenase-2, interleukin-6, and tumor necrosis factor-α in rat basophilic leukemia-2H3 cells. In summary, we isolated dieckol from E. nipponica and demonstrated its antiallergic mechanisms. PRACTICAL APPLICATIONS: As the incidence of allergies increases worldwide, so too does the demand for food components with antiallergic and anti-inflammatory properties. Given this trend, we focused on a brown alga that displays a variety of bioactivities. Here, we have isolated dieckol from the antiallergic lipophilic fraction of E. nipponica and found that it possesses diverse physiological activities that may prevent lifestyle-related diseases. Consequently, dieckol or the alga containing this phlorotannin could be used as a health food ingredient to combat not only allergies, but also variety of disorders including the undesirable effects of aging.

New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5H)ones as Possible Anti-Inflammatory Agents.

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

Echinacea purpurea water extracts suppress the release of chemical mediators from mast cells

Histamine and leukotrienes (LTs), the chemical mediators released from mast cells, play an important role in type-I allergies such as hay fever. Echinacea purpurea (EP) has traditionally been used for herbal tea and has been reported to show biological functions. We evaluated the inhibitory activity of water extracts of EP petals, leaves, and stems against the chemical mediators released from mast cell lines. Petal and leaf extracts exhibited a significant inhibitory effect on histamine release from the stimulated cells, while the stem extract did not exert any effect. Activity of the petal extract was much stronger than that of the leaf extract. All the extracts significantly suppressed LTB4 production in the stimulated cells and displayed similar activities. The petal extract decreased Syk phosphorylation and Ca2+ influx associated with signal transduction in the stimulated cells. These results suggest that EP petal extract may have a relieving effect on allergic symptoms.

The effect of local anesthetic technique on breast cancer - related outcomes: a systematic review

Introduction: Breast cancer is the most incident cancer in women worldwide. A multidisciplinary therapeutic approach may increase survival rates and quality of life, and surgery remains its main support. Surgical removal of the primary tumor occurs with the risk of dispersal of neoplastic cells into the blood and lymphatic systems, as well as the risk of permanence of residual neoplastic cells. Despite curative intent, a combination of perioperative factors leads to a release of chemical mediators that may, paradoxically, be direct or indirectly associated with tumor progression. Local anesthetic technique, as thoracic paravertebral block (TPVB), attenuates neuroendocrine response to surgical stress and may preserve perioperative immune function. Given that surgical stress response seems to increase opportunities for cancer dissemination and metastasis, this anesthetic approach is hypothesized as beneficial to long-term prognosis. The objective of this study was to evaluate the effect of local anesthetic technique on breast cancer-related outcomes in the clinical setting.Methodology: The PubMed database was assessed through Mesh descriptors: “mastectomy”, “mastectomy, radical”, “anesthesia, local”, “recurrence”, “neoplasm recurrence, local”. Reviews, editorials and comments were excluded. The search provided 65 articles, from which 11 were identified as potentially relevant after title and abstract reading. After integral articles analysis, 6 studies were selected.Results: The articles were published from 2006 to 2019, with total samples varying between 129 and 2108 patients. Of these studies, 4 were retrospective, 1 presented a retrospective review of prospective database, and only 1 was a multicenter randomized clinical trial. The average observation time varied between 28.8 to 72 months, and 1 study was stopped after a preplanned futility boundary was crossed. Discussion: The majority of the selected studies are retrospective, being conditioned to the accuracy and availability of the information. Also, some assessed outcomes may be influenced by unmeasured factors, what could be confounding. The majority of the studies did not show improvement in cancer-related outcomes with the usage of TPVB, however, it may reduce the administration of perioperative opioids and be a feasible therapeutic approach to reduce postoperative pain intensity in breast cancer treatment, becoming a relevant intervention to facilitate recovery, accelerate hospital discharge and reduce care costs after the surgery.Conclusion: Although preclinical studies have suggested potential benefits of local anesthesia to reduce cancer recurrence and improve overall survival, this review did not find enough clinical evidence to support thoracic paravertebral block for this purpose in breast cancer surgery. However, local anesthesia may impact the reduction of intraoperative opioid and support pain management in the postoperative period, potentially improving patient’s health-related quality of life.

Abstract 2041: Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model

Abstract Oral cancer is a painful and debilitating type of cancer. Oral cancer patients frequently experience severe pain while eating and talking. Pain is attributed to neuronal sensitization by the release of chemical mediators from the cancer cells and cancer microenvironment. Not all oral cancers are painful. Patients with painful oral cancers are more likely to have worse prognosis and metastatic disease, and their pain is not well managed with NSAIDs or opioid analgesics. Therefore, there is an unmet clinical need to identify the underlying mechanisms of oral cancer pain. This study was designed to identify pathological lesions associated with increased pain in a preclinical model of oral cancer and pain. Forty C57BL/6 female mice were treated with 4-nitroquinoline 1-oxide (4NQO) for 16 weeks, and followed for the development of tongue lesions for 12 weeks. Concurrently, change in nociceptive behavior (i.e., the animal equivalent of pain behavior) was measured using a validated operant assay and device for measuring functional mechanical allodynia (the dolognawmeter). Nociception (pain) scores and histopathological data were obtained from 36 animals. Mice developed a spectrum of tongue and esophageal lesions including hyperkeratoses, papillomas (exophytic lesions), dysplasias and cancers. Papillomas included lesions with benign and dysplastic pathological features, indicating that both lesion types were in the continuum of malignant transformation. Mice harbored lesions associated with low pain scores (n=9), intermediate pain scores (n=16) and high pain scores (n=11). Three pathological subsets of squamous cell carcinomas (SCCs) were identified that displayed stromal invasion (iSCC), deep stromal invasion &amp;gt;1.5mm depth (diSCC) and cancers with exophytic and invasive morphology associated with papillary lesions (pSCCs). Increased nociceptive behavior was associated with pSCCs in univariate and multivariate analyses. Cancers of the pSCC subtype are expected to be enriched for expression and release of nociceptive mediators. The study demonstrates that the 4NQO model recapitulates human cancer with respect to development of cancers differing in level of cancer associated nociception. Citation Format: Keyur Naik, Malvin N. Janal, Jason Chen, Daniel E. Bandary, Branden Brar, Aditi Bhattacharya. Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2041.

Pathophysiological and Genetic Aspects of Vascular Calcification.

Recent evidence suggests that vascular calcification is an independent cardiovascular risk factor (CRF) of morbidity and mortality. New studies point out the existence of a complex physiopathological mechanism that involves inflammation, oxidation, the release of chemical mediators, and genetic factors that promote the osteochondrogenic differentiation of vascular smooth muscle cells (VSMC). This review will evaluate the main mechanisms involved in the pathophysiology and genetics modulation of the process of vascular calcification. Objective. A systematic review of the pathophysiology factors involved in vascular calcification and its genetic influence was performed. Methods. A systematic review was conducted in the Medline and PubMed databases and were searched for studies concerning vascular calcification using the keywords and studies published until 2020/01 in English. Inclusion Criteria. Studies in vitro, animal models, and humans. These include cohort (both retrospective and prospective cohort studies), case-control, cross-sectional, and systematic reviews. Exclusion Criteria. Studies before 2003 of the existing literature.

Clinical, histopathological and immunohistochemical behavior of peri-implant soft tissue.

The presence of foreign materials in the tissues, represented in the present study by the insertion of dental implants, creates artificial structures that can sometimes cause adverse consequences, which implies the obligation to perform a complex medical assessment before inserting dental implants. This assessment appreciates the quality of the tissue, depending on which the use of a certain type of biomaterial is indicated and focuses on a certain surgical technique. We assessed the clinical, histopathological (HP) and immunohistochemical (IHC) aspects of peri-implant soft tissue in patients who did not show mobility or imagistic signs of bone resorption, three months after implant insertion, some of them showing no inflammatory clinical signs. Immunohistochemically, on the sections of the peri-implant mucosa, we assessed the presence of mast cells, vascularization and the process of angiogenesis. Mast cells are key cells actively involved in the pathogenesis of peri-implant inflammation, having an immunomodulatory role. Vasodilation and angiogenesis, determined by the release of chemical mediators by degranulation of mast cells under the action of pathogens, induce tissue remodeling, ensuring the healing and formation of a tissue to form a barrier that effectively prevents the development of a bacterial biofilm. Thus, the control of the activity of these cells is important for the management of the local inflammatory process. The correlations between the clinical, HP and IHC behavior of the peri-implant soft tissue bring important information for the clinic, emphasizing the need to identify a therapeutic strategy to modulate mast cell activity, in order to prevent and treat peri-implant disease, to ensure osseointegration and longer survival of the dental implant.

NADPH oxidase1 inhibition leads to regression of central sensitization during formalin induced acute nociception via attenuation of ERK1/2-NFκB signaling and glial activation

Role of NADPH oxidase1 in the development of inflammatory pain has been demonstrated by gene knockout studies. Nevertheless, pharmacological inhibition of NOX1 is a requisite approach for therapeutic utility. Recently, we have reported the anti-nociceptive effect of newly identified NOX1 specific inhibitor ML171 (2-acetylphenothiazine). Inhibition of NOX1 resulted in attenuation of nociceptive sensitization during acute inflammatory pain via inhibition of ROS generation and its downstream ERK1/2 activation. However, glial activation accompanying inflammation is closely related to the initiation and maintenance of pain. Peripheral nociceptive inputs activate the primary afferents via release of various chemical mediators which are potentially capable of mediating signals from neuron to glia in DRG and subsequently in spinal cord dorsal horn. The subsequent interactions between neuron and glia contribute to pain hypersensitivity. Thus, the present study was focused to investigate the effect of ML171 on ERK1/2 signaling, glial activation, and crosstalk between neuron and glia in a mouse model of formalin induced acute nociception. Thus, the present study was focused to investigate the effect of ML171 on ERK1/2 signaling, glial activation, and crosstalk between neuron and glia in DRG and dorsal horn of the spinal cord of lumbar region (L3-L5) in a mouse model of formalin induced acute nociception.Intraperitoneal administration of ML171 decreased nociceptive behavioral responses, i.e. the flinch and lick counts, in formalin induced nociceptive mice. Immunofluorescence and Western blot analysis demonstrated decreased levels of nociceptive mediators like p-ERK1/2, p-NFκB p65, Iba1 and GFAP in DRG as well as in spinal cord dorsal horn; supporting anti-nociceptive potential of ML171. Further, co-localization studies showed the neuron-glia crosstalk in tissue dependent manner. ERK1/2 was found to be activated in glia and NFκB in neurons in DRG; whereas in case of spinal cord ERK1/2 was activated in neurons and NFκB in astrocytes. Decrease in nociceptive behavioral response and activation of nociceptive mediators after intraperitoneal administration of ML171 strongly advocate anti-nociceptive potential of ML171.This is the first report demonstrating modulation of ERK1/2-NFκB signaling pathway, glial activation and regulation of neuron-glia crosstalk by NADPH oxidase1 inhibition towards its anti-nociceptive action.

Effect of the metanolic extract from the leaves of Garcinia humilis Vahl (Clusiaceae) on acute inflammation.

Garcinia humilis is popularly used to treat digestive, intestinal and inflammatory illness. We investigated the in vivo and in vitro effects of the methanol extract of G. humilis leaves (MEGh) on inflammatory cells behavior (migration and chemical mediators release) and hypersensitivity. Anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice treated orally with MEGh (0.1-30mg/kg). Leucocyte migration, chemical mediators secretion (TNF, IL-1β, IL-6 and CXCL1) and protein exudation were quantified in the exudate. The adhesion molecules expression (CD62L and CD18), chemical mediators and chemotaxis was evaluated using neutrophils or macrophages RAW.264.7 previously treated with the extract (1-100µg/mL) and activated with LPS. The anti-inflammatory activity of the isolated compounds friedelin, canophyllol, amentoflavone and 3-desmethyl-2-geranyl-4-prenylbellidypholine xanthone (10μM) was evaluated in macrophages nitric oxide (NO) and TNF release. MEGh, given orally (30mg/kg), significantly reduced neutrophil migration and decreased TNF, IL-1β and CXCL1 levels, without interfering with protein exudation and IL-6. In vitro, the extract significantly reduced IL-1β and IL-6 levels but did not alter TNF and CXCL1. The MEGh also reduced the expression of CD62L and CD18 and consequently neutrophil chemotaxis. The compounds friedelin, amentoflavone and 3-demethyl-2-geranyl-4-prenylbellidypholine xanthone decreased the secretion of NO and TNF by RAW264.7. The MEGh effects were extended to the pain-like behaviour induced by carrageenan in the mice hindpaw. MEGh presented important anti-inflammatory effects probably due to its activity on neutrophil migration and on important chemical mediator release, scientifically reinforcing its use as medicinal plant.

Associação da disfunção temporomandibular e estresse em militares

The objective of this study was to show, through a review of the literature,the association between occupational stress and temporomandibulardisorder in the military. Nowadays, the high professional competitivenessin the labor market, especially in the military environment, is marked byrigorous principles of hierarchyand discipline, strenuous routines, trainingand even the possibility of involvement inactivities with risk of death. Inthis way, militarism is considered as a stress fuloccupation, which maymake these individuals more susceptible to psychicdisturbances andharmful physiological problems. The effect of stress on the stomatognathicsystem evolves through complex interrelations, resulting in the releaseof chemical mediators that may cause an increase in muscle tone,whichmay secondarily induce changes in the temporomandibular joints,thus contributing to the development of temporomandibular disorder. Inaddition, stress may desensitize structures involved in central nervous systemregulation, contributing toch anges in pain perception of individuals.Therefore, the available evidence in the scientific literature indicates thatmilitary professionals present high levels of boths tress and temporomandibulardysfunction, suggesting a positive association between the two pathologies,however, further studies are needed to define the exactcausalrole of stress on the course and etiology of the dysfunction.

The effect of orthodontic separator and short-term fixed orthodontic appliance on inflammatory mediators and somatosensory function.

Although inflammation can alter cytokines release and nerve function, it is not yet fully established if orthodontic-induced inflammation can cause significant extraoral trigeminal somatosensory alterations and release of inflammatory chemical mediators. The primary aim of this study was to investigate the impact of orthodontic separator and short-term fixed orthodontic appliance on the extraoral trigeminal somatosensory function and concentrations of cytokines in the gingival crevicular fluid (GCF). Twenty-two female patients were evaluated as follow: baseline, 24hour-after elastomeric separator (-aES), 24hour- and 1month-after bonding brackets (-aBB) at both arches. The outcome variables were as follows: self-reported pain (Visual Analog Scale), QSTs (current perception threshold-CPT, cold detection threshold-CDT, warm detection threshold-WDT, mechanical detection threshold-MDT, mechanical suprathreshold-MST and wind-up ratio-WUR. All QSTs were performed at infra-orbital and mental nerve entry zone at patient`s dominant side. In addition, GCF samples in order to assess cytokines profile (IL-1β,IL-8,IL-6 and TNF-α) were collected. ANOVA and Tukey's post hoc analyses were performed (a=5%). Patients reported higher pain intensity 24hour-aBB compared to baseline and 24hour-aES (P<0.050). Patients were less sensitive to pin-prick pain (MST) at 24hour-aBB and 1month-aBB compared to baseline (P<0.006). Significant increases in IL-6 levels were observed 24hour-aBB (P<0.001). Multiple comparison analysis showed significant increase in IL-1β levels (P<0.001) and TNF-α (P<0.001) 1month-aBB compared to baseline. Elastomeric separators only induced mild pain and were not able to significantly increase proinflammatory cytokines level in the GCF. In addition, orthodontic fixed appliance may induce only minor somatosensory changes at extraoral trigeminal locations.