Elevated D-Dimer as a Marker For Thromboembolic Events in Pediatric Patients With Covid-19: A Systematic Review

Abstract Background: The 2019 Coronavirus disease is known to cause thromboembolic events. There is little information on the severe COVID-19 consequences in children. Objectives: To determine whether elevated D-dimer levels in the pediatric population with COVID-19 are a risk marker for the development of thromboembolic events. If so, D-dimer levels could be used to determine prophylactic anticoagulation measures if needed. Methods: This is a systematic review, performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database. The last database search update was on December 14, 2021, resulting in 79 documents for analysis. Data were taken from various databases and queried by topic, keyword, or abstract. Results: Of the 79 articles found, only seven were selected for this analysis. Of these articles, only one had thromboembolic events. In the other articles, D-dimer levels were elevated but were considered controversial in terms of predicting events, with no clear association between the magnitude of D-dimer change and the magnitude of thrombosis risk. Conclusions: Although used for adults, D-dimer was not a good parameter for assessing the risk of thromboembolic events in individuals younger than 21 years. The main shortcomings are the fact that D-dimer increases with any type of inflammation and is, therefore, not a specific marker, and that it is elevated in many patients even without the occurrence of thromboembolic events.

JumpSTART Triage Protocol in Disaster Pediatric Patients: A Systematic Literature Review.

INTRODUCTION: In a mass-casualty incident (MCI) involving children, there is a need to apply accurate triage tools in order to help those who require important care, and at the same time, to avoid unnecessary use of resources. Thus, it is discussed which would be the best triage device to use in these situations. One of the most used is a modification of Simple Triage and Rapid Treatment, JumpSTART, whose performative quality this review focuses on. STUDY OBJECTIVE: This review sought to compare the performance parameters of JumpSTART with other triage algorithms used in pediatric disaster victims. METHODS: This systematic review was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered with the PROSPERO database of systematic reviews with the number CRD42021258415. The last update of the search in the databases was on August 12, 2021 and resulted in six documents to be analyzed. The inclusion criteria included the peer-reviewed academic papers in English, Portuguese, Spanish, and Italian languages, and the databases used were PubMed, Scopus, MEDLINE/Bireme (Virtual Library of Health), Web of Science, and CINAHL, which executes the query on the topic, keywords, or abstracts. Also to be included, documents that were available with full-text access through CAPES, Google, or Google Scholar. Books, non-academic research, and content in languages other than the presented ones were represented as exclusion criteria. The Joanna Briggs Institute (JBI) checklists were used to evaluate the methodological quality of the retrieved studies. The results were presented through narrative synthesis. This review was not funded. RESULTS: Of the collected publications, five articles were used to carry out this review, with the addition of an extra article captured by citation tracking. The findings from the obtained results were that JumpSTART was the preferred tool and presented the fastest speed of use. Only one of the five studies that dealt with accuracy showed JumpSTART as the most accurate algorithm, while three of the other four showed its inferiority in most aspects. In one study, no significant difference was observed amongst the chosen protocols. CONCLUSIONS: There is insufficient evidence to validate JumpSTART as a universal triage tool, given the disparities in the results obtained from the comparisons. No tool performed satisfactorily well, therefore there is an urgent need to create a reliable algorithm.

Children's Health Care in Mass-Casualty Incidents: A Systematic Literature Review.

OBJECTIVES: Considering the pediatric peculiarities and the difficulty of assisting this population in mass-casualty situations, this study aims to identify the main topics regarding children's health care in mass-casualty incidents (MCIs) that are discussed in the Emergency Medicine area. METHODS: This systematic review was performed according to the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and registered with the PROSPERO database of systematic reviews with the number CRD42021229552. The last update of the search in the databases was on May 27, 2021 and resulted in 45 documents to be analyzed. The inclusion criteria included the peer-reviewed academic papers in English, Portuguese, Spanish, and Italian languages; the databases used were PubMed, Scopus, MEDLINE/Bireme (Virtual Library of Health - VLH), and Web of Science, which execute the query on the topic, keywords, or abstracts. Also, to be included, documents that were available with full-text access through CAPES, Google, or Google Scholar. Books, non-academic research, and content in languages other than the presented ones were represented as exclusion criteria. RESULTS: From the resulting papers, 21 articles served as the basis for this analysis. Revealed were the year of publication, the first author's institution nationality, topic, and disaster management phase for each study, which allow other researchers to understand the main topics regarding children's health care in MCIs. CONCLUSIONS: The topics regarding child's health care in MCIs found in the primary studies of this review, in order of frequency, were: Disaster Response (including the following sub-topics: simulation, education, quality of care, use of technological tools, and damage analysis); Triage; and Disaster Planning. The Emergency Medicine operation was focused on harm reduction after the occurrence of an MCI. Further studies focusing on the pre-disaster and post-disaster phases are needed.

Involvement of Opioid System and TRPM8/TRPA1 Channels in the Antinociceptive Effect of Spirulina platensis.

Spirulina platensis is a "super-food" and has attracted researchers' attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3-300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.

Bradykinin Receptors Play a Critical Role in the Chronic Post-ischaemia Pain Model.

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.

Antidepressant-Like Effect of Terpineol in an Inflammatory Model of Depression: Involvement of the Cannabinoid System and D2 Dopamine Receptor.

Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a ß-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.

Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways.

Citral ((2E)-3,7-dimethylocta-2,6-dienal), a bioactive component of lemongrass, inhibits oxidant activity, nuclear factor kappa B (NF-κB) activation, and cyclooxygenase-2 (COX-2) expression, even as it activates peroxisome proliferator-activated receptor (PPAR)-α and γ. Additionally, citral produces long-lasting inhibition of transient receptor potential (TRP) channels that are found in sensory neurons, such as TRPV1-3 and TRPM8, while it transiently blocks TRPV4 and TRPA1. Here, the effect of citral in experimental models of acute inflammation and hyperalgesia in mice, and the underlying citral mechanisms of action were investigated. ADMET properties and molecular targets were predicted using the online server. The immunomodulatory and antihyperalgesic effects of citral were evaluated, using mechanical and thermal stimuli, at different time-points on carrageenan, lipopolysaccharides (LPS), and zymosan-induced paw edema and hyperalgesia in mice. ADMET analysis ensures that the citral has not violated Lipinski's rule of five, indicating its safety consumption, and molecular target prediction software identified that citral is a potential fatty acid amide hydrolase (FAAH) inhibitor. Oral treatment with citral (50-300 mg/kg) significantly inhibited carrageenan-induced paw edema and thermal allodynia. Furthermore, citral modulated the inflammation induced by LPS and zymosan, toll-like receptor (TLR) 4, and TLR2/dectin-1 ligands, respectively. Moreover, pretreatment with cannabinoid receptor type 2 (CB2R) antagonists and ATP-sensitive K+ channel inhibitor, but not with a cannabinoid receptor type 1 (CB1R) antagonist, significantly reversed the anti-inflammatory effect of citral. Intriguingly, citral did not cause any relevant action in the central nervous system, and it was safe when assessed in a 14 day toxicity assay in male mice. Therefore, citral constitutes a promising, innovative, and safe molecule for the management of immunoinflammatory conditions and pain states.

Photobiomodulation Therapy Improves Acute Inflammatory Response in Mice: the Role of Cannabinoid Receptors/ATP-Sensitive K+ Channel/p38-MAPK Signalling Pathway.

Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM. Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively. Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice. Graphical Abstract ᅟ.

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I.

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.

Physical Exercise Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Peripheral Immune Response and Blood-Brain Barrier Disruption.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) caused by demyelination, immune cell infiltration, and axonal damage. Herein, we sought to investigate the influence of physical exercise on mice experimental autoimmune encephalomyelitis (EAE), a reported MS model. Data show that both strength and endurance training protocols consistently prevented clinical signs of EAE and decreased oxidative stress, an effect which was likely due to improving genomic antioxidant defense-nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response elements (ARE) pathway-in the CNS. In addition, physical exercise inhibited the production of pro-inflammatory cytokines interferon (IFN)-γ, interleukin (IL)-17, and IL-1ß in the spinal cord of mice with EAE. Of note, spleen cells obtained from strength training group incubated with MOG35-55 showed a significant upregulation of CD25 and IL-10 levels, with a decrease of IL-6, MCP-1, and tumor necrosis factor (TNF)-α production, mainly, during acute and chronic phase of EAE. Moreover, these immunomodulatory effects of exercise were associated with reduced expression of adhesion molecules, especially of platelet and endothelial cell adhesion molecule 1 (PECAM-1). Finally, physical exercise also restored the expression of tight junctions in spinal cord. Together, these results demonstrate that mild/moderate physical exercise, when performed regularly in mice, consistently attenuates the progression and pathological hallmarks of EAE, thereby representing an important non-pharmacological intervention for the improvement of immune-mediated diseases such as MS. Graphical Abstract Schematic diagram illustrating the beneficial effects of physical exercise during experimental model of MS. Physical exercise, especially strength (ST) and endurance (ET) training protocols, inhibits the development and progression of disease, measured by the mean maximal clinical score (1.5 and 1.0, respectively), with inhibition of 30 % and 50 %, respectively, based on the AUC, compared with EAEuntreated group. In addition, ST and ET decreased oxidative stress, possibly, through genomic antioxidant defense, Nrf2-Keap1 signaling pathway, in the CNS. Physical exercise inhibited the production of inflammatory cytokines, such as IFN-γ, IL-17 and IL-1ß in the spinal cord after EAE induction, as well as spleen cells obtained from ST group showed a significant upregulation of regulatory T cell markers, such as CD25 and IL-10 levels, and blocked IL-6, MCP-1 and TNF-α production, mainly, during acute and chronic phase of EAE. Finally, these immunomodulatory effects of exercise were associated with inhibition of adhesion molecules and reestablishment of tight junctions expression in spinal cord tissue, thereby limiting BBB permeability and transmigration of autoreactive T cells to the CNS. NO, nitric oxide; GPx, glutathione peroxidase, GSH, glutathione; Nrf2, nuclear factor (erythroid-derived 2)-like 2; CNS, central nervous system; BBB, blood-brain barrier; IFN-g, interferon-gamma; IL-17, interleukin 17; IL-1b, interleukin-1beta.

Healing, antioxidant and cytoprotective properties of Indigofera truxillensis in different models of gastric ulcer in rats.

The present study evaluated the antiulcerogenic activity and mechanisms of the aqueous (AqF 100 mg/kg) and ethyl acetate (AcF 50 mg/kg) fractions from Indigofera truxillensis leaves. This dose was selected to assess its activity on ulcer healing and its action on gastric acid and mucus secretion, prostaglandin production and antioxidant enzyme activity (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd)). Gastric ulcer was induced by absolute ethanol. Antisecretory action, mucus and prostaglandin production, healing and antioxidant enzyme activities were evaluated for both fractions. AqF and AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant at 100 and 50 mg/kg compared with the vehicle. Neither fraction interfered with gastric secretion. AcF increased the PGE(2) production, and both fractions increased mucus production. l-NAME did not alter the gastroprotection exerted by the fractions, but N-ethylmaleimide attenuated only AcF. In the ischemia/reperfusion model both fractions inhibited the mucosal damage. AcF increased SOD, GSH-Px and GSH-Rd activity, but AqF increased only SOD and GSH-Px. In the acetic acid-induced ulcer model AcF only accelerated ulcer healing. These results showed that Indigofera truxillensis acted as a gastroprotective agent, stimulating protective factors and antioxidants enzymes.

Evaluation of chemical mediators and cellular response during acute and chronic gut inflammatory response induced by dextran sodium sulfate in mice.

Inflammatory bowel disease (IBD) affects millions of people worldwide but its pathophysiology remains unclear. Therefore, experimental models of colitis have contributed crucially for the understanding of IBD, and also in the investigations for effective therapies. Herein we investigated the kinetics of inflammatory mediator production and cell infiltration during acute and chronic dextran sodium sulfate (DSS)-induced colitis. The induction phases with DSS were characterized by severe disease activity with massive colonic polymorphonuclear infiltration and increased levels of tumor necrosis factor-α (TNF-α), keratinocyte-derived chemokine (CXCL1/KC), interleukin (IL)-17 and vascular adhesion molecule-1 (VCAM-1). Interestingly, in the recovery periods, we found marked increase of anti-inflammatory mediators IL-10, IL-4, transforming growth factor-ß (TGF-ß) and cyclooxygenase 2 (COX-2) that seems be essential for the resolution of intestinal inflammation. Furthermore, nuclear factor κB (NFκB) and regulatory T cell marker forkhead box P3 (FoxP3) were increased gradually during experimental colitis, demonstrating a discrepant profile response and evident immune disbalance in the chronic phase of intestinal mucosal inflammation. Taken together, these results provide valuable information for studies on DSS-induced colitis and especially for the identification of biomarkers that predict disease course and possible therapeutic interventions.

Activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice.

In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

Anti-ulcerogenic mechanisms of the sesquiterpene lactone onopordopicrin-enriched fraction from Arctium lappa L. (Asteraceae): role of somatostatin, gastrin, and endogenous sulfhydryls and nitric oxide.

Arctium lappa L. has been used in folk medicine as a diuretic, depurative, and digestive stimulant and in dermatological conditions. The mechanisms involved in the anti-ulcerogenic activity of the sesquiterpene onopordopicrin (ONP)-enriched fraction (termed the ONP fraction), obtained from A. lappa leaves, were studied. The gastroprotective mechanism of the ONP fraction was evaluated in experimental in vivo models in rodents, mimicking this disease in humans. ONP fraction (50 mg/kg, p.o.) significantly inhibited the mucosal injury induced by ethanol/HCl solution (75%), indomethacin/bethanecol (68.9%), and stress (58.3%). When the ONP fraction was investigated in pylorus ligature, it did not induce alteration in the gastric volume but did modify the pH and total acid concentration of gastric juice. ONP fraction significantly increased serum somatostatin levels (82.1±4.1 vs. control group 12.7±4 pmol/L) and decreased serum gastrin levels (62.6±6.04 vs. control group 361.5±8.2 µU/mL). Mucus production was not significantly altered by the ONP fraction. Gastroprotection by the ONP fraction was completely inhibited by N-ethylmaleimide treatment and did not modify the effect in the animals pretreated with l-N(G)-nitroarginine methyl ester. These results suggest an antisecretory mechanism involved with the antiulcerogenic effect of the ONP fraction. However, only endogenous sulfhydryls play an important role in gastroprotection of the ONP fraction.

Indigofera suffruticosa Mill as new source of healing agent: involvement of prostaglandin and mucus and heat shock proteins.

ETHNOPHARMACOLOGICAL RELEVANCE: Indigofera suffruticosa is specie typical of the "Cerrado" or Brazilian savannah; it is a member of the Fabaceae family - in folkmedicine is used for gastric disorders, infection and inflammation. AIM OF THE STUDY: Ethyl acetate fraction (AcF) and aqueous fraction (AqF) of the methanolic extract of I. suffruticosa leaves were evaluated against acute gastric ulcer. The AcF fraction was selected to assess its activity in ulcer healing and its gastroprotective effects via mucus and gastric secretion. MATERIALS AND METHODS: The gastroprotective action of AcF and AqF fractions were evaluated in a rodent experimental model. The action mechanisms, involvements of the antisecretory action, mucus and prostaglandin production, toxicological and healing activity of the AcF (100mg/kg, p.o.) were evaluated. We also used histological analysis (HE and PAS) and immunohistochemical (PCNA and HSP-70) assays to evaluate the effects of I. suffruticosa. RESULTS: AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant in 100mg/kg group compared vehicle. AcF did not interfered with gastric secretion, significantly increased the PGE(2) and mucus production (validated in PAS technique). The gastroprotection was attenuated by pretreatment with N-ethylmaleimide, but not L-NAME. In acid-acetic-induced ulcer model AcF accelerated ulcer healing. Immunohistochemistry analysis showed induction of proliferating cell (PCNA) and heat shock protein (HSP 70). CONCLUSIONS: These results showed that AcF acted as gastroprotective agent stimulating prostaglandin, mucus and HSP70.

ß-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway.

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-ß-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1ß, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/ß, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease.

Mechanisms of the gastric antiulcerogenic activity of Anacardium humile St. Hil on ethanol-induced acute gastric mucosal injury in rats.

Leaves and bark infusions Anacardium humile St. Hil. (Anacardiaceae), known as in Brazil as "cajuzinho do cerrado", have been used in folk medicine as an alternative treatment for ulcers and gastritis. This study evaluated the gastroprotective activity of an ethyl acetate extract of the leaves of A. humile (AcF) and the mechanism involved in this gastroprotection. Pretreatment concentrations (50, 100, 200 mg x kg⁻¹) were administered by gavage. Following a 60 min. period, all the rats were orally administered 1 mL of absolute ethanol. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated. Prostaglandin PGE2 concentration, gastric adherent mucous, and the participation of nitric oxide (NO) and sulfhydryl compounds in the gastroprotection process were also analyzed using the most effective tested dose (50 mg x kg⁻¹). A histological study of the glandular stomach for the evaluation of the epithelial damage and mucus content was also performed. AcF significantly reduced the gastric damage produced by ethanol. This effect was statistically significant for the 50 mg x kg⁻¹ group compared to control. Also, it significantly increased the PGE2 (by 10-fold) and mucous production, while pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM) completely abolished the gastroprotection. AcF has a protective effect against ethanol, and this effect, might be due to the augmentation of the protective mechanisms of mucosa.

The anti-ulcerogenic effects of Curatella americana L.

ETHNOPHARMACOLOGICAL RELEVANCE: Curatella americana L. (Dilleneaceae) is a medicinal plant very frequently cited as acting against gastrointestinal disorders in ethnopharmacological inventories of the Cerrado region of Brazil. AIM OF THE STUDY: The ethanolic extract (CEB) and infusion (BI) of Curatella americana bark were investigated for their ability to prevent and heal ulceration of the gastric mucosa. MATERIALS AND METHODS: The preventive and healing actions of Curatella americana were evaluated in experimental in vivo models in rodents that simulated this disease in human gastric mucosa. RESULTS: CEB significantly decreased the severity of gastric damage formation induced by the combination of several gastroprotective models (HCl/ethanol, indomethacin/bethanecol, absolute ethanol, stress and pylorus ligature). But, unlike CEB, the BI did not exert gastroprotective effect. The gastroprotective action of CEB involved antisecretory action, augmentation of gastric mucus (48%) and participation of endogenous sulfhydryl compounds that increase efficacy of barrier mucosa against injurious agents. CEB also presents effective healing action in chronic gastric disease (1.90+/-0.55 vs. 6.86+/-0.46 mm2)in the control) and its action mechanisms consisted of increasing the PGE2 (40%) and somatostatin levels (269%) while decreasing the gastrin level in rat plasma (79%). CONCLUSIONS: The gastroprotective effect and healing action of Curatella americana involved modulation of PGE2, somatostatin and gastrin levels, probably due to the presence of oligomeric and polymeric proanthocyanidins in the bark.

Antioxidant activity of indigo and its preventive effect against ethanol-induced DNA damage in rat gastric mucosa.

Ethanol-induced oxidative damage is commonly associated with the generation of reactive oxygen molecules, leading to oxidative stress. Considering that antioxidant activity is an important mechanism of action involved in cytoprotection, the aim of this work was to evaluate the antioxidant properties of the alkaloid indigo (1) (2 mg/kg, P. O.), obtained from the leaves of Indigofera truxillensis Kunth (Fabaceae), on rat gastric mucosa submitted to ethanol-induced (100%, 1 mL, P. O.) gastric ulcer. Enzymatic assays and DNA fragmentation analysis were performed. When ethanol was administered to the control group, the sulfhydryl content (SH) and the glutathione peroxidase (GPx) activity decreased by 41% and 50%, respectively; in contrast, superoxide dismutase (SOD) and glutathione reductase (GR) activities increased by 56% and 67%, respectively. Additionally, myeloperoxidase (MPO) activity, a marker for free radical generation caused by polymorphonuclear neutrophil (PMN) tissue infiltration, also increased 4.5-fold after ethanol treatment. Rat gastric mucosa exposed to ethanol showed DNA fragmentation. Indigo alkaloid pretreatment protected rats from ethanol-induced gastric lesions. This effect was determined by the ulcerative lesion area (ULA), indicating an inhibition of around 80% at 2 mg/kg. This alkaloid also diminished GPx activity, which was higher than that observed with ethanol alone. However, this effect was counterbalanced by increased GR activity. Indigo was unable to restore alterations in SOD activity promoted by ethanol. After indigo pretreatment, SH levels and MPO activity remained normal and gastric mucosa DNA damage caused by ethanol was also partially prevented by indigo. These results suggest that the gastroprotective mechanisms of indigo include non-enzymatic antioxidant effects and the inhibition of PMN infiltration which, in combination, partially protect the gastric mucosa against ethanol-induced DNA damage.

Vernonia polyanthes as a new source of antiulcer drugs.

Methanolic (VPME) and chloroformic (VPCL) extracts, obtained from the aerial parts of Vernonia polyanthes, were investigated for its antiulcerogenic properties. Administration of VPME (250 mg/kg) and VPCL (50 mg/kg) significantly inhibited the gastric mucosa damage (64% and 90%, respectively) caused by absolute ethanol (p.o.). Otherwise, in NSAID-induced gastric damage, their gastroprotective effects have decreased. Since the VPCL extract resulted to be more effective than the VPME we focused our efforts over VPCL action mechanism of action.