Resolution of Lipopolysaccharide-Induced Inflammation Followed by DNA Hypomethylation and Increased Tetrahydrobiopterin Biosynthesis in Mouse Hippocampus Jennyffer Souza, Debora da Luz Scheffer, Alexandre Francisco Solano, Samantha Veloso, Luisa Cruz, Rodrigo Foganholi-Silva, Alexandra Latini Brain Sciences, 2025 Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide (LPS) in the mouse hippocampus. Methods: Male C57BL/6J mice received either saline or LPS (0.33 mg/kg, i.p.) and were sacrificed at 4 h or 24 h post injection. Behavioral assessments and analyses of hippocampal neurotransmitter metabolism, DNA methylation profile, oxidative stress, and inflammasome activation were performed. Neopterin levels, a marker of immune system activation, were measured in both the plasma and hippocampus. Results: LPS-treated mice exhibited sickness behavior, including reduced locomotor and exploratory activity at both 4 and 24 h. While exploratory behavior showed partial recovery by 24 h, locomotor activity remained impaired. Neopterin levels increased in both the plasma and hippocampus following LPS administration but returned to baseline in the hippocampus by 24 h. Despite the normalization of neopterin, a persistent pro-inflammatory state in the hippocampus was evident at 24 h, as shown by increased expression of Ikbkb and components of the NLRP3 inflammasome, along with elevated oxidative stress markers. Upregulation of Nrf-2 and Hmox1 suggested activation of a protective antioxidant response. Dopaminergic metabolism was disrupted, indicating impaired BH4-dependent dopamine turnover. Epigenetic analysis revealed increased expression of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) and Tet2, along with reduced expression of Tet1 and Tet3. Promoter hypomethylation of Gch1 and Ptps was observed, correlating with increased hippocampal expression and potentially elevated BH4 levels. Conclusions: Together, these findings show that a single LPS challenge was sufficient to induce the activation of the BH4 synthesis pathway during the late acute inflammatory phase, both systemically and in the hippocampus, potentially driven by epigenetic modifications such as promoter hypomethylation. This may contribute to the perpetuation of neuroinflammation.
Anti-Inflammatory Effect of Caffeine on Muscle under Lipopolysaccharide-Induced Inflammation Tuany Eichwald, Alexandre Francisco Solano, Jennyffer Souza, Taís Browne de Miranda, Liebert Bernardes Carvalho, Paula Lemes dos Santos Sanna, Rodrigo A. Foganholi da Silva, Alexandra Latini Antioxidants, 2023 Evidence has shown that caffeine administration reduces pro-inflammatory biomarkers, delaying fatigue and improving endurance performance. This study examined the effects of caffeine administration on the expression of inflammatory-, adenosine receptor- (the targets of caffeine), epigenetic-, and oxidative metabolism-linked genes in the vastus lateralis muscle of mice submitted to lipopolysaccharide (LPS)-induced inflammation. We showed that caffeine pre-treatment before LPS administration reduced the expression of Il1b, Il6, and Tnfa, and increased Il10 and Il13. The negative modulation of the inflammatory response induced by caffeine involved the reduction of inflammasome components, Asc and Casp1, promoting an anti-inflammatory scenario. Caffeine treatment per se promoted the upregulation of adenosinergic receptors, Adora1 and Adora2A, an effect that was counterbalanced by LPS. Moreover, there was observed a marked Adora2A promoter hypermethylation, which could represent a compensatory response towards the increased Adora2A expression. Though caffeine administration did not alter DNA methylation patterns, the expression of DNA demethylating enzymes, Tet1 and Tet2, was increased in mice receiving Caffeine+LPS, when compared with the basal condition. Finally, caffeine administration attenuated the LPS-induced catabolic state, by rescuing basal levels of Ampk expression. Altogether, the anti-inflammatory effects of caffeine in the muscle can be mediated by modifications on the epigenetic landscape.
Fish injuries resulting from transient operating conditions in a Brazilian hydropower plant: morphological, physiological and biochemical evaluation in Pimelodus maculatus (Siluriformes: Pimelodidae) Janaína dos Santos Pedron, Jurandir Joaquim Bernardes Junior, Josiane Ribolli, Jennyffer Souza, Aline Guimarães Pereira, Hugo Tolentino, Romuel Barros, Carine de Freitas Milarch, Rafael José Gonçalves Dias, Renata Maria Guereschi, Alexandra Latini, Alex Pires de Oliveira Nuñer Neotropical Ichthyology, 2023 This study investigated injuries sustained by Pimelodus maculatus caused by transient operating conditions in a Brazilian hydroelectric power plant. Fish (n = 43) that inhabited the tailrace and appeared on the water surface after changes in the operating conditions were evaluated (IF). Additionally, fish (n = 10) captured using longline in the vicinity of the tailrace were used for comparisons (NF). Blood samples were evaluated for cortisol, glucose, and lactate concentrations. Tissue samples (gill, liver, brain, and muscle) were analyzed for oxidative stress biomarkers (TBARS, protein carbonyl content, and catalase activity) and histology (gill, liver, and spleen). The most prominent findings in IF were barotraumas with intra-abdominal hemorrhage and swim bladder rupture. Cortisol and glucose concentrations were lower for IF when compared to NF. IF also suffered from oxidative stress, as indicated by increased TBARS in the liver and brain, as well as increased protein carbonyl content in the gills and liver. The main histological alterations induced by the adverse conditions were circulatory disorders, such as telangiectasia and gill aneurysm, hepatic congested veins, and hemorrhage in the liver and spleen. The abrupt drop of pressure resulting from changes in the operating conditions of the turbines caused barotraumas and oxidative stress, which were the leading causes of fish mortality
Physical-Exercise-Induced Antioxidant Effects on the Brain and Skeletal Muscle Jennyffer Souza, Rodrigo Augusto da Silva, Débora da Luz Scheffer, Rafael Penteado, Alexandre Solano, Leonardo Barros, Henning Budde, Andrés Trostchansky, Alexandra Latini Antioxidants, 2022 Erythroid-related nuclear factor 2 (NRF2) and the antioxidant-responsive-elements (ARE) signaling pathway are the master regulators of cell antioxidant defenses, playing a key role in maintaining cellular homeostasis, a scenario in which proper mitochondrial function is essential. Increasing evidence indicates that the regular practice of physical exercise increases cellular antioxidant defenses by activating NRF2 signaling. This manuscript reviewed classic and ongoing research on the beneficial effects of exercise on the antioxidant system in both the brain and skeletal muscle.
Anti-inflammatory and antioxidant properties of Alternanthera brasiliana improve cutaneous wound healing in rats Rogério Marchete, Sarah Oliveira, Leonardo Bagne, Jennyffer Ione de Souza Silva, Ana Paula Valverde, Andrea Aparecida de Aro, Mariana Moreira Figueira, Marcio Fronza, Thainá Mikaela Bressam, Vivian Fernandes Furletti de Goes, Fernanda Oliveira de Gaspari de Gaspi, Gláucia Maria Tech dos Santos, Thiago Antônio Moretti Andrade Inflammopharmacology, 2021
Effects of the Association between Photobiomodulation and Hyaluronic Acid Linked Gold Nanoparticles in Wound Healing Carolini Mendes, Daniela Pacheco dos Santos Haupenthal, Rubya Pereira Zaccaron, Gustavo de Bem Silveira, Maria Eduarda Anastácio Borges Corrêa, Laura de Roch Casagrande, Samara de Sousa Mariano, Jennyffer Ione de Souza Silva, Thiago Antônio Moretti de Andrade, Paulo Emilio Feuser, Ricardo Andrez Machado-de-Ávila, Paulo Cesar Lock Silveira ACS Biomaterials Science and Engineering, 2020 Healing is the process responsible for restoring the integrity of the body's internal or external structures when they rupture. Photobiomodulation (PBM) stands out as one of the most efficient resources in the treatment of epithelial lesions, as well as hyaluronic acid (HA), which has been emerging as a new molecule for the treatment of dermal and epidermal lesions. The biological application of gold nanoparticles (GNPs) shows promising results. This study aimed to investigate the possible anti-inflammatory and antioxidant effects of the association between PBM and GNPs-linked HA in an epithelial lesion model. Fifty Wistar rats were randomly distributed in the Control Group (CG); (PBM); (PBM + HA); (PBM + GNPs); (PBM + GNPs-HA). The animals were anesthetized, trichotomized, and induced to a surgical incision in the dorsal region. Topical treatment with HA (0.9%) and/or GNPs (30 mg/kg) occurred daily associated with 904 nm laser irradiation, dose of 5 J/cm2, which started 24 h after the lesion and was performed daily until the seventh day. The levels of proinflammatory (IL1 and TNFα), anti-inflammatory (IL10 and IL4) and growth factors (FGF and TGFβ) cytokines and oxidative stress parameters were evaluated, besides histological analysis through inflammatory infiltrate, fibroblasts, new vessels, and collagen production area. Finally, for the analysis of wound size reduction, digital images were performed and subsequently analyzed by the IMAGEJ software. The treated groups showed a decrease in proinflammatory cytokine levels and an increase in anti-inflammatory cytokines. TGFβ and FGF levels also increased in the treated groups, especially in the combination therapy group (PBM + GNPs-HA). Regarding the oxidative stress parameters, MPO, DCF, and Nitrite levels decreased in the treated groups, as well as the oxidative damage (Carbonyl and Thiol groups). In contrast, antioxidant defense increased in the groups with the appropriate therapies proposed compared to the control group. Histological sections were analyzed where the inflammatory infiltrate was lower in the PBM + GNPs-HA group. The number of fibroblasts was higher in the PBM and PBM + HA treated groups, whereas collagen production was higher in all treated groups. Finally, in the analysis of the wound area contraction, the injury group presented a larger area in cm2 compared to the other groups. Taken together, these results allow us to observe that the combination of PBM + GNPs-HA optimized the secretion of anti-inflammatory cytokines, proliferation and cell differentiation growth factors, and made an earlier transition to the chronic phase, contributing to the repair process.
RECENT SCHOLAR PUBLICATIONS
Adora2A downregulation promotes caffeine neuroprotective effect against LPS-induced neuroinflammation in the hippocampus PL dos Santos Sanna, LB Carvalho, CC dos Santos Afonso, ... Brain Research 1833, 148866 , 2024 2024 Citations: 12
Fish injuries resulting from transient operating conditions in a Brazilian hydropower plant: morphological, physiological and biochemical evaluation in Pimelodus maculatus … JS Pedron, JJ Bernardes Junior, J Ribolli, J Souza, AG Pereira, ... Neotropical Ichthyology 21, e220104 , 2023 2023 Citations: 4
Anti-inflammatory effect of caffeine on muscle under lipopolysaccharide-induced inflammation T Eichwald, AF Solano, J Souza, TB de Miranda, LB Carvalho, ... Antioxidants 12 (3), 554 , 2023 2023 Citations: 22
Anti-Inflammatory Effect of Caffeine on Muscle under Lipopolysaccharide-Induced Inflammation. Antioxidants 2023, 12, 554 T Eichwald, AF Solano, J Souza, TB de Miranda, LB Carvalho, ... 2023
Optimization of differential ultracentrifugation for the purification of small extracellular vesicles from human biological fluids R SILVA, J SOUZA, A PRIGOL, L KAWANO-DOURADO, A LATINI ELSEVIER SCIENCE INC , 2023 2023
Janaína dos Santos Pedron1, Jurandir Joaquim Bernardes Junior1, Josiane Ribolli1, Jennyffer Souza2, Aline Guimarães Pereira2, Hugo Tolentino2, Romuel Barros2, Carine de Freitas … B Baldisserotto Neotropical Ichthyology 21 (3), e220104 , 2023 2023
Role of Tetrahydrobiopterin Metabolism in Abdominal Pain in Inflammatory Bowel Diseases T Pasa, A Latini, J Souza, B Lenfers, L Cruz, A Staats, S Rizzati, L Niero, ... Free Radical Biology and Medicine 192, 32 , 2022 2022
Physical-exercise-induced antioxidant effects on the brain and skeletal muscle J Souza, RA da Silva, D da Luz Scheffer, R Penteado, A Solano, L Barros, ... Antioxidants 11 (5), 826 , 2022 2022 Citations: 56
Anti-inflammatory and antioxidant properties of Alternanthera brasiliana improve cutaneous wound healing in rats R Marchete, S Oliveira, L Bagne, JIS Silva, AP Valverde, AA Aro, ... Inflammopharmacology 29 (5), 1443-1458 , 2021 2021 Citations: 29
Argon atmospheric plasma treatment promotes burn healing by stimulating inflammation and controlling the redox state LB Souza, JIS Silva, L Bagne, AT Pereira, MA Oliveira, BB Lopes, ... Inflammation 43 (6), 2357-2371 , 2020 2020 Citations: 23
Effects of percutaneous collagen induction therapy associated with hyaluronic acid on inflammatory response, oxidative stress, and collagen production MEAB Corrêa, DP dos Santos Haupenthal, C Mendes, RP Zaccaron, ... Inflammation 43, 2232-2244 , 2020 2020 Citations: 17
Effects of the association between photobiomodulation and hyaluronic acid linked gold nanoparticles in wound healing C Mendes, DP dos Santos Haupenthal, RP Zaccaron, G de Bem Silveira, ... ACS Biomaterials Science & Engineering 6 (9), 5132-5144 , 2020 2020 Citations: 45
Deficient Hippocampal AMPK Phosphorylation and Unfitted Mitochondria Underlie Hyperglycemia-induced Cognitive Impairment A Remor, M da Silva, F Martins, J Souza, V Glaser, N Lucredi, L Barros, ... FREE RADICAL BIOLOGY AND MEDICINE 145, S103-S103 , 2019 2019
MOST CITED SCHOLAR PUBLICATIONS
Physical-exercise-induced antioxidant effects on the brain and skeletal muscle J Souza, RA da Silva, D da Luz Scheffer, R Penteado, A Solano, L Barros, ... Antioxidants 11 (5), 826 , 2022 2022 Citations: 56
Effects of the association between photobiomodulation and hyaluronic acid linked gold nanoparticles in wound healing C Mendes, DP dos Santos Haupenthal, RP Zaccaron, G de Bem Silveira, ... ACS Biomaterials Science & Engineering 6 (9), 5132-5144 , 2020 2020 Citations: 45
Anti-inflammatory and antioxidant properties of Alternanthera brasiliana improve cutaneous wound healing in rats R Marchete, S Oliveira, L Bagne, JIS Silva, AP Valverde, AA Aro, ... Inflammopharmacology 29 (5), 1443-1458 , 2021 2021 Citations: 29
Argon atmospheric plasma treatment promotes burn healing by stimulating inflammation and controlling the redox state LB Souza, JIS Silva, L Bagne, AT Pereira, MA Oliveira, BB Lopes, ... Inflammation 43 (6), 2357-2371 , 2020 2020 Citations: 23
Anti-inflammatory effect of caffeine on muscle under lipopolysaccharide-induced inflammation T Eichwald, AF Solano, J Souza, TB de Miranda, LB Carvalho, ... Antioxidants 12 (3), 554 , 2023 2023 Citations: 22
Effects of percutaneous collagen induction therapy associated with hyaluronic acid on inflammatory response, oxidative stress, and collagen production MEAB Corrêa, DP dos Santos Haupenthal, C Mendes, RP Zaccaron, ... Inflammation 43, 2232-2244 , 2020 2020 Citations: 17
Adora2A downregulation promotes caffeine neuroprotective effect against LPS-induced neuroinflammation in the hippocampus PL dos Santos Sanna, LB Carvalho, CC dos Santos Afonso, ... Brain Research 1833, 148866 , 2024 2024 Citations: 12
Fish injuries resulting from transient operating conditions in a Brazilian hydropower plant: morphological, physiological and biochemical evaluation in Pimelodus maculatus … JS Pedron, JJ Bernardes Junior, J Ribolli, J Souza, AG Pereira, ... Neotropical Ichthyology 21, e220104 , 2023 2023 Citations: 4
Anti-Inflammatory Effect of Caffeine on Muscle under Lipopolysaccharide-Induced Inflammation. Antioxidants 2023, 12, 554 T Eichwald, AF Solano, J Souza, TB de Miranda, LB Carvalho, ... 2023
Optimization of differential ultracentrifugation for the purification of small extracellular vesicles from human biological fluids R SILVA, J SOUZA, A PRIGOL, L KAWANO-DOURADO, A LATINI ELSEVIER SCIENCE INC , 2023 2023
Janaína dos Santos Pedron1, Jurandir Joaquim Bernardes Junior1, Josiane Ribolli1, Jennyffer Souza2, Aline Guimarães Pereira2, Hugo Tolentino2, Romuel Barros2, Carine de Freitas … B Baldisserotto Neotropical Ichthyology 21 (3), e220104 , 2023 2023
Role of Tetrahydrobiopterin Metabolism in Abdominal Pain in Inflammatory Bowel Diseases T Pasa, A Latini, J Souza, B Lenfers, L Cruz, A Staats, S Rizzati, L Niero, ... Free Radical Biology and Medicine 192, 32 , 2022 2022
Deficient Hippocampal AMPK Phosphorylation and Unfitted Mitochondria Underlie Hyperglycemia-induced Cognitive Impairment A Remor, M da Silva, F Martins, J Souza, V Glaser, N Lucredi, L Barros, ... FREE RADICAL BIOLOGY AND MEDICINE 145, S103-S103 , 2019 2019
