HIGHLIGHTS Latex from P. pudica contains molecules with pro (DLPp) and anti-inflammatory activities (LPPp). DLPp pro-inflammatory activity depended on the administered dose and could be inhibited by the LPPp. Pro-inflammatory activity of DLPp is related to histamine-like molecules in the fraction. Antihistaminic drugs can be used to treat inflammation associated with P. pudica latex exposure.

BACKGROUND:Periodontitis affects millions of people and is characterized by the accumulation of bacteria in the gingival sulcus with an immune-inflammatory response of the body causing effects. There is a notable relation between periodontitis and steatosis, in which caspase-8 may be a relevant player in the pathophysiology of these conditions. This study is the first to investigate the effect of treatment based on Lactobacillus sp. on steatosis and caspase-8 expression in a ligature-induced periodontitis model. This study aims to investigate whether treatment with Lactobacillus sp. reduces oral and hepatic changes caused by ligature-induced periodontitis. METHODOLOGY:Twenty-four Wistar rats were separated into groups: control, periodontitis, and periodontitis plus Lactobacillus sp. Administration of 1 mL of fermented milk containing 108 CFU/mL of Lactobacillus sp. by gavage was performed daily for 20 days of ligature-induced periodontitis. After the treatment, we evaluated the gingival bleeding index (GBI), tooth mobility, probing pocket depth (PPD), alveolar bone loss, histomorphometry, and histopathological aspects of liver, as well as the levels of glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO). We also evaluated caspase-8-positive cells and blood biomarkers. RESULTS:Lactobacillus sp. reduced inflammatory clinical parameters, including GBI, PPD, and tooth mobility, as well as neutrophil infiltration in gingival tissue. Morphometric analysis showed significantly less alveolar bone loss. Analysis of hepatic tissue showed reduced neutrophilic infiltration and improved antioxidant activity. Treatment also decreased caspase-8 expression. CONCLUSIONS:Lactobacillus sp. significantly reduced the clinical parameters of periodontal lesion and steatosis score, improved hepatic oxidative status, and decreased caspase-8 expression in the liver tissue.

Plant galactomannan extracted from the endosperm of Libidibia ferrea seeds is characterized by high viscosity and rich phenolic composition with antioxidant potential and enzymatic activity, being useful in the food industry and pharmaceutical formulations. Therefore, this study aimed to evaluate the anti-inflammatory and antioxidant effect of a polysaccharide extracted from Libidibia ferrea seeds (PLS-Lf) in models of acute inflammation. PLS-Lf was characterized as galactomannan, which has a main chain formed by β(1 → 4)d-mannopyranosyl units with α-(1 → 6)-d-galactopyranosyl branches. The animals received PLS-Lf at doses of 1.0, 3.0 and 10 mg/kg. The 10 mg/kg dose of PLS-Lf showed the best effect among all doses tested, significantly reducing edema induced by carrageenan, histamine, serotonin and prostaglandin E2. In addition, it was able to significantly reduce leukocyte migration to the peritoneal cavity and the concentration of the enzyme myeloperoxidase, malondialdehyde, and preserve glutathione levels. In the nociception test, it significantly reduced the paw licking time induced by formalin in both phases of the test. The data suggest that this PLS-Lf is an important pharmacological tool to study the anti-inflammatory properties of natural drug candidates with therapeutic potential against inflammatory diseases.

Ulcerative colitis is a chronic inflammatory condition of the gastrointestinal tract, and new therapeutic strategies targeting specific molecular pathways are of great interest. This study evaluated the anti-inflammatory effect of epiisopiloturine, an imidazole alkaloid, in acetic acid-induced colitis in mice, with focus on the role of the type M1 muscarinic acetylcholine receptor. Molecular docking revealed a strong binding affinity between epiisopiloturine and this cholinergic receptor subtype (-8.44 ΔG (kcal/mol)). Colitis was induced with 6

The liver is particularly susceptible to damage during biotransformation. Drug-induced liver injury (DILI) is a necroinflammatory condition that can progress to severe liver failure. Drugs containing nitroaromatic groups, such as nimesulide, are associated with hepatotoxicity due to the formation of reactive metabolites that increase oxidative stress and bind to proteins and genetic material, thereby causing liver damage. This model represents the classic explanation of nimesulide-induced hepatotoxicity, which is mainly based on the molecular mechanisms involved in the dysregulation of oxidant-antioxidant homeostasis and mitochondrial dysfunction, followed by direct cellular damage. However, this approach does not fully explain the heterogeneity of the disease or its possible progression. The involvement of immune-mediated mechanisms remains unclear. Although there is no direct evidence demonstrating that nimesulide specifically induces the release of damage-associated molecular patterns (DAMPs), the involvement of these danger signals is biologically plausible in the current context of DILI, which recognizes the need for a co-stimulatory signal to sustain the immune response, possibly DAMPs released by the damaged hepatocytes. Thus, we propose that the idiosyncratic hepatotoxicity of nimesulide is caused by its metabolic bioactivation via cytochrome P450. The resulting reactive metabolites act as initial mechanical triggers for the release of the alarmin S100A8/A9, activating the RAGE receptor on Kupffer cells and triggering NF-kappa B signaling activation. This activation may increase iNOS expression, promoting sustained nitric oxide production and nitrosative stress and establishing an inflammatory amplification cycle that potentiates hepatotoxicity.

Inflammatory bowel disease (IBD) comprises two distinct forms, Crohn's disease and ulcerative colitis, characterized by their chronicity and multifactorial pathophysiology, resulting in an exacerbated inflammatory response and release of inflammatory mediators, promoting cell destruction in the gastrointestinal tract (GIT). This chronic intestinal inflammation promotes structural and functional changes in the enteric nervous system, mainly in GI tract glial cells. In IBD, excessive activation of immune cells and overexpression of pro-inflammatory cytokines can lead to enteric neuronal death and pathological activation of enteric glial cells, playing an important role in intestinal neuroimmunomodulation, resulting in the inflammatory process, loss of function, and release of inflammatory mediators such as S100(3 protein, capable of interacting with the RAGE receptor, activating NF-kappa B, favoring the transcription of several pro-inflammatory cytokines, such as TNF-alpha and IL-1(3, which triggers neurodegeneration. Studies show that chronic activation of RAGE can result in intestinal dysfunction and neuron death, contributing to the motor and sensory disorders observed in IBD. In contrast, the endocannabinoid system regulates intestinal homeostasis, modulates the inflammatory process, and consequently maintains intestinal balance. The interaction between enteric glial cells and cannabinoids also influences the process of gliosis, which is attributed to its beneficial effects in IBD. The CB1 and CB2 cannabinoid receptors present in immune cells and enteric neurons may act to maintain the integrity of the intestinal barrier and neuronal survival, suggesting that this mechanism may have a therapeutic role in IBD treatment.

This study aimed to develop a bromelain-based gel and evaluate its effects in a ligature-induced periodontitis model in rats. The bromelain-based gel was formulated in two concentrations (1% and 10%). Ten animals were used per group: Control, Periodontitis, Periodontitis + Neutral Gel, Periodontitis + 1% Bromelain Gel, Periodontitis + 10% Bromelain Gel and Periodontitis + 2% Chlorhexidine Gel. The clinical parameters of tooth mobility (TM), gingival bleeding index (GBI) and probing pocket depth (PPD) were evaluated and, after euthanasia, gingival and liver tissue were collected by biopsy for biochemical evaluation of myeloperoxidase (MPO), malonaldehyde (MDA), glutathione (GSH) and from the jaws for morphometric analysis of alveolar bone height. The clinical parameters of MT, GBI and PPD of the groups treated with bromelain gel showed a significant reduction (MT = 67.04%, GBI = 67.72% and PPD = 41.22%) compared to the group with periodontitis. The results for MPO dosage in the gingival tissue showed statistically significant differences between the groups when compared to the group with periodontitis, MDA and GSH showed promising results in the groups treated with gels in the dosages of gingival and liver tissue. The results for ABL showed significant differences when compared to the groups that received gel treatment. Therefore, the bromelain orabase gel evaluated in periodontitis showed a positive response for the following parameters TM, GBI and PPD, MPO, MDA and ABL of the oral tissues, preventing alveolar bone resorption caused by the disease, highlighting the potential as an adjuvant treatment of periodontitis, in addition to reducing the systemic effects on the liver tissue.

Resident immune cells are involved in the pathogenesis of inflammatory bowel diseases (IBDs). Studies have already demonstrated that these cells, mainly mast cells and macrophages, are close to and in communication with neurons of the enteric nervous system (ENS). Enteric neurons organized in ganglions participate in processes such as control of motility, secretory functions, absorption and blood flow. Morphological and functional changes in these neurons can cause intestinal damage, such as changes in intestinal motility and diarrhea, common features of IBD. Uncontrolled or unregulated activation of mast cells can also interfere with intestinal homeostasis and generate tissue dysfunction and promote inflammation in various gastrointestinal diseases. These cells can also act by releasing mediators that activate enteric glial cells (EGC), leading to reactive gliosis. Despite being recognized as essential regulators of neuronal function in the ENS, when activated by injuries and inflammatory processes, these cells can proliferate and undergo broad activation that, in association with other cells of the external muscular layer of the intestine (neutrophils, monocytes, resident macrophages and smooth muscles) produces and releases pro-inflammatory mediators. This pro-inflammatory action also involves the participation of the beta fraction of the calcium-binding protein S100 (S100 beta), which despite being found in other cells, in the intestine its expression is limited to EGC. The increase in the expression of this protein may be responsible for the death of neurons, through the activation of receptors for advanced glycation end products (RAGE) and consequent activation of the nuclear transcription factor-kappa B (NF kappa B). RAGE-type receptors are expressed in several cells, including their presence in macrophages. It is known that interactions between macrophages and the ENS interfere with intestinal motility, serve as a protective mechanism during injuries and infections, but can also contribute to tissue damage and other gastrointestinal disorders. Therefore, our hypothesis suggests that mast cells and macrophages, resident immune cells, are involved in enteric neuronal death, through the activation of EGCs and the release of pro-inflammatory factors.

Seaweeds are natural sources of sulfated polysaccharides (SPs), biopolymers with remarkable pharmacological properties, including biological actions capable of attenuating components of the inflammatory process such as edema, cytokines, cell migration and pain. Our results confirm that SPs obtained from Gracilaria domingensis (SP-GD) are agarans, primarily composed of residues of β-d-galactopyranose 6-sulfate and 3,6-anhydro-α-l-galactopyranose. Specifically, SP-GD at a dose of 10 mg/kg was effective in significantly reducing paw edema induced by carrageenan or histamine, serotonin, bradykinin, 48/80 and prostaglandin E2. SP-GD (10 mg/kg) was also able to reduce neutrophil migration and the activity of the myeloperoxidase enzyme in carrageenan-induced peritonitis, as well as conserve glutathione concentration and reduce malondialdehyde levels in the animals' peritoneal fluid. Furthermore, it showed antinociceptive action in the abdominal writhing test induced by acetic acid and in the paw licking test induced by formalin. Thus, the results obtained allow us to infer that SPs extracted from G. domingensis at a dose of 10 mg/kg have anti-inflammatory effects by reducing neutrophil migration and modulating the activity of vasoactive mediators and antinociceptive effects by acting, at least in part, through a peripheral mechanism dependent on the negative modulation of inflammatory mediators.

The crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system was investigated during acetic acid-induced experimental colitis. In this research, male mice were treated with the agonist M1 receptor McN-A-343 (1.5 mg/kg; intraperitoneal) or dexamethasone (2.0 mg/kg; subcutaneous) 17 h or 17 h 30 min after the induction of acetic acid colitis, respectively. The cannabinoid receptor antagonists, CB1 (AM251, 3.0 mg/kg, intraperitoneal) and CB2 (AM630, 1.0 mg/kg, intraperitoneal), were administered 30 min before McN-A-343 and dimethyl sulfoxide (DMSO, 4 %, intraperitoneal) at the same time as the antagonists. After 18 h of colitis induction, 5 cm of the distal part of the colon was collected for analysis of macroscopic and microscopic lesion scores, intestinal wet weight, biochemical measurements: concentration of myeloperoxidase, tumor necrosis fator alpha (TNF-α), interleukin-1β (IL-1β), malondialdehyde, reduced glutathione, nitrate/nitrite and protein expression of Nf-κB (Nuclear Factor-κBp65), inducible nitric oxide (iNOs) and cyclooxygenases 2 (Cox-2) by Western Blotting. Administration of AM251 or AM630 before treatment with McN-A-343 significantly altered the anti-inflammatory response of the agonist M1 receptor, evidenced by the accentuation of intestinal damage, increased wet weight, myeloperoxidase levels, pro-inflammatory cytokines, oxidative stress markers and protein expression of NF-κB, iNOs and Cox-2. These results suggest that CB1 and CB2 receptors are involved in the anti-inflammatory action of McN-A-343 in experimentally induced colitis. Therefore, the crosstalk between these systems may present promising potential for treatment of intestinal inflammatory conditions.

Sulfated polysaccharides (PLSs) from marine algae represent a broad class of compounds with pharmacological interest, due to their therapeutic properties. PLSs have hydrophilic chains containing various chemical groups of several compositions that differ structurally and in their physicochemical and biological effects. However, this hydrophilic nature of PLSs is also responsible for some limitations in the use of these compounds. To overcome these disadvantages, PLSs can be chemically modified by grafting groups that can give the compound a more hydrophobic nature. In the present study, the PLS from Gracilaria domingensis was modified with propionic anhydride (PLS-AP) and underwent complementary characterizations by scanning electron microscopy, X-ray diffraction, infrared spectral analysis and elemental analysis. The reaction with propionic anhydride increased crystallinity and produced a chemically modified polysaccharide with new carbon, hydrogen and sulfur groups. The new characteristic of the compound may have added interesting properties to PLS, such as increased stability, amphiphilic nature and increased sulfate content, which in red marine algae SPSs produce biological activity. Regarding biological properties, PLS-AP (2.5 mg/kg) significantly reduced paw edema induced by carrageenan, histamine, serotonin, bradykinin and prostaglandin E2, as well as improved microscopic tissue damage criteria. The modified compound was also able to significantly decrease neutrophil migration, myeloperoxidase, and malondialdehyde concentrations and preserved glutathione levels in peritoneal fluid during induced peritonitis. Additionally, in antinociceptive tests, PLS-AP reduced the number of contortions induced by acetic acid and the response time to formalin-induced paw licking. Thus, PLS-AP may be a promising substance to treat inflammatory conditions.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in therapy due to their anti-inflammatory and analgesic properties. However, their clinical use is often associated with gastrointestinal complications. Thus, this study aimed to investigate the protective effect of a sulfated iota-carrageenan isolated from the marine alga Solieria filiformis (IC-Sf) against naproxen-induced gastrointestinal injury. Methods: Parameters of gastrointestinal injury, secretory and motor functions, and toxicity were evaluated. Results: The results demonstrated that IC-Sf significantly reduced naproxen-induced gastrointestinal macroscopic injury, with a maximum effect observed at 30 mg/kg. IC-Sf also preserved gastrointestinal antioxidant defense and prevented lipid peroxidation, with a reduction in the non-protein sulfhydryl group (NP-SH) and malondialdehyde (MDA) concentrations induced by naproxen. Additionally, IC-Sf mitigated naproxen-induced gastrointestinal inflammation, as evidenced by reduced myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). IC-Sf did not alter gastric secretion or gastrointestinal motility. In addition, the animals treated with IC-Sf did not present toxic effects. Conclusions: In conclusion, IC-Sf protected the gastrointestinal tract against the harmful effects of naproxen by inhibiting the inflammatory response and lipid peroxidation, suggesting its potential as a new therapeutic agent or food additive.

Ethnopharmacological relevance: The plants of the genus Casimirella ampla (Miers) (C. ampla) are extensively used in folk medicine. For a long time, rural communities have been using extracts from its roots for food and therapeutic purposes. The extract is rich in diterpenoid annonalide (Annona), which has antiophidic, antiinflammatory and antinociceptive properties. Inflammation is the body's primary defense mechanism against cell damage and invasion by pathogens, which can trigger acute and chronic inflammatory processes. The first line of treatment for this condition consists of the use of non-steroidal anti-inflammatory drugs, but these have numerous associated collateral damages, based on scientific knowledge about diterpenoids from C. ampla, as well as their already reported antinociceptive and anti-inflammatory properties. Aims of the study: Evaluate the effect of Annona in classic models of inflammation and pain. Materials and methods: Animals were pretreated with Annona (0.1, 1.0 and 10 mg/kg), or Tween 80 (2%), or indomethacin (Indo) (10 mg/kg) orally in the paw edema tests induced by carrageenan (Cg), serotonin (5-HT), histamine, bradykinin, 48/80 and, prostaglandin E2 (PGE2), evaluating microscopic lesion scores, migration of leukocytes to the peritoneal cavity, concentration of myeloperoxide (MPO), malonyldialdehyde (MDA) and glutathione (GSH), abdominal contortion test by acetic acid and formalin test. Results: Treatment with Annona compound at a dose of 0.1 mg/kg was more effective in reducing inflammatory, oxidant and nociceptive parameters, as it reduced paw edema induced by carrageenan, through different mediators and migration of inflammatory cells. Furthermore, it worked by reducing the concentration of MPO, MDA, preserving GSH levels and reducing nociception caused by formalin and acetic acid.

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1β; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.