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Metabolic alterations are increasingly recognized as important aspects of colorectal cancer (CRC), offering potential avenues for identifying therapeutic targets. Previous studies have demonstrated the cytotoxic potential of bamboo leaf extract obtained from Guadua incana (BLEGI) against HCT-116 colon cancer cells. However, the altered metabolic pathways in these tumor cells remain unknown. Therefore, this study aimed to employ an untargeted metabolomic approach to reveal the metabolic alterations of the endometabolome and exometabolome of HCT-116 cells upon exposure to BLEGI treatment. First, a chemical characterization of the BLEGI was conducted through liquid chromatography coupled with mass spectrometry (LC-MS). Next, we assessed cell viability via MTT and morphological analysis using an immunofluorescence assay against colon cancer cells, and anti-inflammatory activity using an LPS-stimulated macrophage model. Subsequently, we employed LC-MS and proton nuclear magnetic resonance (1H-NMR) to investigate intra- and extracellular changes. Chemical characterization primarily revealed the presence of compounds with a flavone glycoside scaffold. Immunofluorescence analysis showed condensed chromatin and subsequent formation of apoptotic bodies, suggesting cell death by apoptosis. The results of the metabolomic analysis showed 98 differential metabolites, involved in glutathione, tricarboxylic acid cycle, and lipoic acid metabolism, among others. Additionally, BLEGI demonstrated significant nitric oxide (NO) inhibitory capacity in macrophage cells. This study enhances our understanding of BLEGI's possible mechanism of action and provides fresh insights into therapeutic targets for treating this disease.

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INTRODUCTION: Furoxan and benzofuroxan are compounds containing an N-oxide function, known for their diverse pharmacological properties, including antimicrobial and antiinflammatory effects. This study aimed to investigate these activities using an in-house library of N-oxide compounds. METHOD: Twenty compounds were tested against both Gram-positive and Gram-negative bacteria, including Cutibacterium acnes (C. acnes), a microorganism implicated in the development of acne vulgaris. One compound, (E)-4-(3-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3- (phenylsulfonyl)-1,2,5-oxadiazol-2-N-oxide (compound 15), exhibited selective antimicrobial activity against C. acnes, with a Minimum Inhibitory Concentration (MIC) value of 2 µg/mL. Indirect measurement of Nitric Oxide (NO) release showed that compound 15 and isosorbide dinitrate, when treated with L-cysteine, produced nitrite levels of 20.1% and 9.95%, respectively. Using a NO scavenger (PTIO) in combination with compound 15 in a culture of C. acnes resulted in reduced antimicrobial activity, indicating that NO release is part of its mechanism of action. Cytotoxicity assessments using murine macrophages showed cellular viability above 70% at concentrations up to 0.78 µg/mL. RESULTS: Measurements of Interleukin-1 beta (IL1-ß) and Tumor Necrosis Factor-alpha (TNF-α) indicated that compound 15 did not reduce the levels of these pro-inflammatory cytokines. Sustained NO production by inducible Nitric Oxide Synthase (iNOS) in macrophages or neutrophils has been found to be involved in the inflammatory process in acne vulgaris and lead to toxicity in surrounding tissues. Nitrite levels in the supernatant of murine macrophages were found to be decreased at a concentration of 0.78 µg/mL of compound 15, indicating an anti-inflammatory effect. In vivo studies were conducted using Balb/c nude mice inoculated subcutaneously with C. acnes. Cream and gel formulations of compound 15 were applied to treat the animals, along with commercially available anti-acne drugs, for 14 days. Animals treated with a cream base containing 5% of compound 15 exhibited less acanthosis with mild inflammatory infiltration compared to other groups, highlighting its anti-inflammatory properties. CONCLUSION: Similar results were observed in the benzoyl peroxide group, demonstrating that compound 15 presented comparable anti-inflammatory activity to the FDA-approved drug. These promising results suggest that compound 15 has a dual mechanism of action, with selective antimicrobial activity against C. acnes and notable anti-inflammatory properties, making it a potential prototype for developing new treatments for acne vulgaris.

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Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental Trypanossoma cruzi acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of T. cruzi. Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by T. cruzi infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the T. cruzi-infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi. These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection.

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Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 6-7 million people worldwide. The dichloromethane extract obtained from the aerial parts of Gymnocoronis spilanthoides var subcordata showed trypanocidal activity in vitro. The fractionation of the dewaxed organic extract via column chromatography led to the isolation of three diterpenoids: ent-9α,11α-dihydroxy-15-oxo-kaur-16-en-19-oic acid or adenostemmoic acid B, (16R)-ent-11α-hydroxy-15-oxokauran-19-oic acid and ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic acid. These compounds showed IC50 values of 10.6, 15.9 and 4.8 µM against T. cruzi epimastigotes, respectively. When tested against amastigotes, the diterpenoids afforded IC50 values of 6.1, 19.5 and 60.6 µM, respectively. The cytotoxicity of the compounds was tested on mammalian cells using an MTT assay, resulting in CC50s of 321.8, 23.3 and 14.8 µM, respectively. The effect of adenostemmoic acid B on T. cruzi was examined at the ultrastructural level using transmission microscopy. Treatment with 20 µM for 48 h stimulated the formation of abnormal cytosolic membranous structures in the parasite. This compound also showed an anti-inflammatory effect in murine macrophages stimulated with LPS and other TLR agonists. Treatment of macrophages with adenostemmoic acid B was able to reduce TNF secretion and nitric oxide production, while increasing IL-10 production. The combination of adenostemmoic acid B with benznidazole resulted in greater inhibition of NF-kB and a decrease in nitrite concentration. The administration of adenostemmoic acid B to mice infected with trypomastigotes of T. cruzi at the dose of 1 mg/kg/day for five days produced a significant decrease in parasitemia levels and weight loss. Treatment with the association with benznidazole increased the survival time of the animals. In view of these results, adenostemmoic acid B could be considered a promising candidate for further studies in the search for new treatments for Chagas disease.

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Diketopiperazine alkaloids have proven the most abundant heterocyclic alkaloids up to now, which usually process diverse scaffolds and rich biological activities. In our search for bioactive diketopiperazine alkaloids from marine-derived fungi, two novel diketopiperazine alkaloids, penipiperazine A (1) and its biogenetically related new metabolite (2), together with a known analogue neofipiperzine C (3), were obtained from the strain Penicillium brasilianum. Their planar structures and absolute configurations were elucidated by extensive spectroscopic analyses, 13C NMR calculation, Marfey's, ECD, and ORD methods. Compound 1 featured a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system, and its plausible biogenetic pathway was also proposed. Additionally, compounds 1-3 have been tested for their inflammatory activities. 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells, suggesting they could be attracting candidate for further development as anti-inflammatory agent. KEY POINTS: • A novel diketopiperazine alkaloid featuring a unique 6/5/6/6/5 indole-pyrazino-pyrazino-pyrrolo system was isolated from the marine fungus Penicillium brasilianum. • The structure of 1 was elucidated by detailed analysis of 2D NMR data, 13C NMR calculation, Marfey's, ECD, and ORD methods. • Compounds 1 and 2 significantly inhibited the release of NO and the expression of related pro-inflammatory cytokines on LPS-stimulated RAW264.7 cells.

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Steatosis is characterized by fat accumulation and insulin resistance (IR) in hepatocytes, which triggers a pro-oxidant, pro-inflammatory environment that may eventually lead to cirrhosis or liver carcinoma. This work was aimed to assess the effect of Sechium edule root hydroalcoholic extract (rSe-HA) (rich in cinnamic and coumaric acid, among other phenolic compounds) on triglyceride esterification, lipid degradation, AMPK expression, and the phosphorylation of insulin receptor in a Ser312 residue, as well as on the redox status, malondialdehyde (MDA) production, and the production of proinflammatory cytokines in an in vitro model of steatosis induced by oleic acid, to help develop a phytomedicine that could reverse this pathology. rSe-HA reduced triglyceride levels in hepatocyte lysates, increased lipolysis by activating AMPK at Thr172, and improved the redox status, as evidenced by the concentration of glycerol and formazan, respectively. It also prevented insulin resistance (IR), as measured by glucose consumption and the phosphorylation of the insulin receptor at Ser312. It also prevented TNFα and IL6 production and decreased the levels of MDA and nitric oxide (ON). Our results indicate that rSe-HA reversed steatosis and controlled the proinflammatory and prooxidant environment in oleic acid-induced dysfunctional HepG2 hepatocytes, supporting its potential use to control this disorder.

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Silk fibroin is a fibrillar protein obtained from arthropods such as mulberry and non-mulberry silkworms. Silk fibroin has been used as a dressing in wound treatment for its physical, chemical, mechanical, and biological properties. This systematic review analyzed studies from PubMed, Web of Science, and Scopus databases to identify the molecules preferred for functionalizing silk fibroin-based dressings and to describe their mechanisms of exhibiting anti-inflammatory and antibacterial properties. The analysis of the selected articles allowed us to classify the dressings into different conformations, such as membranes, films, hydrogels, sponges, and bioadhesives. The incorporation of various molecules, including antibiotics, natural products, peptides, nanocomposites, nanoparticles, secondary metabolites, growth factors, and cytokines, has allowed the development of dressings that promote wound healing with antibacterial and immunomodulatory properties. In addition, silk fibroin-based dressings have been established to have the potential to regenerate wounds such as venous ulcers, arterial ulcers, diabetic foot, third-degree burns, and neoplastic ulcers. Evaluation of the efficacy of silk fibroin-based dressings in tissue engineering is an area of great activity that has shown significant advances in recent years.

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ETHNOPHARMACOLOGICAL RELEVANCE: Mimosa caesalpiniifolia (Sansão-do-Campo) is a native species of the caatinga in northeastern Brazil that has been studied for its potential anti-inflammatory and antidepressant activity. It is popularly consumed as a medicinal plant and its pharmacological benefits are evidenced in the literature. AIM OF THE STUDY: The present work was carried out to promote the chemical profile and evaluate the pharmacological activity of the dry extract and the ethyl acetate fraction obtained from the dry leaves of Mimosa caesalpiniifolia. MATERIALS AND METHODS: The leaves were collected in the municipality of Alfenas-MG and subjected to drying, followed by division in a knife mill. The preparation of the dry extract was carried out by the extraction method using simple percolation and the fraction was obtained by liquid-liquid partition. Part of the extractive solution was concentrated in a rotary evaporator followed by a drying process using the spray technique with the addition of colloidal silicon dioxide. The dry extract (33.33%) showed a higher yield in mass when compared to the yield of the ethyl acetate fraction (19.67%). The in vivo pharmacological evaluation was conducted with a total of 82 male Wistar rats that underwent cecal ligation and perforation surgery to induce the inflammatory process. One week after surgery, these animals were treated for 7 days with the dry extract and the ethyl acetate fraction and submitted to behavioral tests (open field and forced swimming). RESULTS: The chemical results were obtained through analysis by HPLC-PDA coupled to a mass spectrometer, enabling the verification of the presence of phenolic acids, flavonoids, aglycones, and glycosides, in addition to tannins. This corroborates with data present in the literature for the genus Mimosa sp. Some compounds had their structure determined, where they were identified as catechin (m/z 288.97), cassiaocidentalin A (m/z 560.75), and procyanidin B2 [(epi)catechin-(epi)catechin; m/z 576.83)]. It was found that the animals that were submitted to the treatment did not present statistically significant results, demonstrating that the pharmacological action evaluated in the test was not highlighted in this type of experiment. The groups that underwent treatment had an aggravated locomotor activity. CONCLUSIONS: The results found with the chemical study contributed to the knowledge of the plant species studied. On the other hand, further studies are needed to provide a better understanding of the pharmacological evaluation of Mimosa caesalpiniifolia.

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Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.

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Many species from Myrtaceae have traditionally been used in traditional medicine as anti-inflammatory, antimicrobial, antidiarrheal, antioxidant and antirheumatic, besides in blood cholesterol reduction. In the present work, the anti-inflammatory activity of essential oils from eighteen Myrtaceae spp. were evaluated according to their ex-vivo anti-inflammatory activity in human blood, and the corresponding biomarkers were determined using untargeted metabolomics data and multivariate data analysis. From these studied species, six displayed anti-inflammatory activity with percentage rates of inhibition of PGE2 release above 70%. Caryophyllene oxide (1), humulene epoxide II (2), ß-selinene (3), α-amorphene (4), α-selinene (5), germacrene A (6), ß-bisabolene (7), α-muurolene (8), α-humulene (9), ß-gurjunene (10), myrcene (11), ß-elemene (12), α-cadinol (13), α-copaene (14), E-nerolidol (15) and ledol (16) were annotated as potential anti-inflammatory biomarkers. The results obtained in this study point to essential oils from species of the Myrtaceae family as a rich source of anti-inflammatory agents.