Arthroplasty is an orthopedic surgical procedure that replaces a dysfunctional joint by an orthopedic prosthesis, thereby restoring joint function. Upon the use of the joint prosthesis, a wearing process begins, which releases components such as titanium dioxide (TiO₂) that trigger an immune response in the periprosthetic tissue, leading to arthritis, arthroplasty failure, and the need for revision. Flavonoids belong to a class of natural polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Hesperidin methyl chalcone’s (HMC) analgesic, anti-inflammatory, and antioxidant effects have been investigated in some models, but its activity against the arthritis caused by prosthesis-wearing molecules, such as TiO₂, has not been investigated. Mice were treated with HMC (100 mg/kg, intraperitoneally (i.p.)) 24 h after intra-articular injection of 3 mg/joint of TiO₂, which was used to induce chronic arthritis. HMC inhibited mechanical hyperalgesia, thermal hyperalgesia, joint edema, leukocyte recruitment, and oxidative stress in the knee joint (alterations in gp91^phox, GSH, superoxide anion, and lipid peroxidation) and in recruited leukocytes (total reactive oxygen species and GSH); reduced patellar proteoglycan degradation; and decreased pro-inflammatory cytokine production. HMC also reduced the activation of nociceptor-sensory TRPV1⁺ and TRPA1⁺ neurons. These effects occurred without renal, hepatic, or gastric damage. Thus, HMC reduces arthritis triggered by TiO₂, a component released upon wearing of prosthesis.

The immune response is essential in the protection of our body against pathogens; however, the inflammatory response caused by the immune system can become a disease itself. In fact, anti-inflammatory and immune-suppressive drugs are applied to limit the immune response to treat inflammatory diseases. Flavonoids are plant-derived polyphenols extensively investigated for their anti-inflammatory and antioxidant properties in inflammatory diseases. Studies applying isolated compounds as well as using supplements as nutraceuticals based on flavonoids have been conducted. Our review systematically analyzed the top five studied flavonoids between 2020 and 2025: quercetin (1742 articles), kaempferol (642), luteolin (589), apigenin (419), and epicatechin (354), highlighting their major therapeutic applications in diseases affecting the liver (12%), nervous system (11%), and lungs (10%). Mechanistically, these compounds act as multi-target agents mainly by inhibiting NF-κB and inducing Nrf2-dependent antioxidant programs. Application of advanced delivery systems, which increase oral bioavailability by up to 20-fold, overcomes pharmacokinetic bottlenecks. Clinical highlights demonstrated promising therapeutic effects, including reduced intrahepatic lipid accumulation in non-alcoholic fatty liver disease patients following quercetin supplementation (11.5% to 9.6%) and accelerated SARS-CoV-2 clearance after quercetin phytosome administration. The translation of flavonoids into standardized clinical therapies remains limited by the lack of large-scale, well-controlled clinical trials.

UVB skin pathology is initiated by reactive oxygen species (ROS), differentiating this condition from other inflammatory diseases involving first the immune cell activation by danger or pathogen molecular patterns followed by oxidative stress. Resolvin D2 (RvD2) has been found to reduce inflammation in preclinical models. However, whether or not RvD2 reduces skin pathology caused by UVB irradiation is not yet known. Therefore, the efficacy of RvD2 on skin pathology triggered by UVB irradiation in female hairless mice was assessed. RvD2 (0.3, 1 or 3 ng/mouse, i.p.) was found to protect the skin against UVB inflammation, as observed in the reduction in edema (46%), myeloperoxidase activity (77%), metalloproteinase-9 activity (39%), recruitment of neutrophils/macrophages (lysozyme⁺ cells, 76%) and mast cells (106%), epidermal thickening (93%), sunburn cell formation (68%), collagen fiber breakdown (55%), and production of cytokines such as TNF-α (100%). Considering the relevance of oxidative stress to UVB irradiation skin pathologies, an important observation was that the skin antioxidant capacity was recovered by RvD2 according to the results that show the ferric reducing antioxidant power (68%), cationic radical scavenges (93%), catalase activity (74%), and the levels of reduced glutathione (48%). Oxidative damage was also attenuated, as observed in the reduction in superoxide anion production (69%) and lipid hydroperoxides (71%). The RvD2 mechanism involved the inhibition of NF-κB activation, as observed in the diminished degradation of IκBα (48%) coupled with a reduction in its downstream targets that are involved in inflammation and oxidative stress, such as COX-2 (66%) and gp91^phox (77%) mRNA expression. In conclusion, RvD2 mitigates the inflammatory and oxidative pathologic skin aggression that is triggered by UVB.

The venom of Bothrops jararaca (BjV) induces intense and prolonged pain, which is not alleviated by antivenom, along with hemorrhage and inflammation. In this study, we investigated the effects of the specialized pro-resolving lipid mediator (SPM) maresin 2 (MaR2) in a murine model of BjV-evoked pain and inflammation. Mice received a single intraperitoneal (i.p.) injection of MaR2 30 min before the intraplantar BjV injection. MaR2 treatment significantly attenuated mechanical (electronic aesthesiometer) and thermal (hot plate) hyperalgesia in a dose-dependent manner. Additionally, MaR2 restored the balance for the hind-paw static weight distribution. When BjV (0.01, 0.1, and 1 μg) stimulus was administered intraperitoneally, pre-treatment with MaR2 (0.3, 1, or 3 ng) ameliorated mechanical and thermal hyperalgesia in a dose-dependent manner. Moreover, MaR2 (3 ng) effectively reduced the levels of myeloperoxidase activity and cytokines (TNF-α, IL-1β, and IL-6) and superoxide anion (O₂^•−) production induced by intraplantar injection of BjV while enhancing total antioxidant levels (ABTS scavenging). For the peritonitis model induced by BjV, MaR2 pretreatment decreased leukocyte recruitment, hemorrhage, nitric oxide (NO), and O₂^•− generation and gp91phox and inducible nitric oxide synthase (iNOS) mRNA expression. In conclusion, this study presents the first evidence that MaR2 effectively mitigated BjV-induced pain, hemorrhage, and inflammation.

Potassium superoxide (KO₂), a superoxide anion donor, can be applied to induce reactive oxygen species (ROS) triggered pain and inflammation. trans-Chalcone (TC) is an atypical flavonoid because its molecular structure does not possess intrinsic antioxidant properties. This characteristic allows investigating the mechanisms of action of flavonoids excluding inherent chemical antioxidant effect. In the present study, we investigated the activity and mechanisms of TC in a model of inflammation and pain triggered by a superoxide anion donor, which to our knowledge have not been assessed yet. Overt pain-like behavior, mechanical hyperalgesia, edema, leukocyte recruitment, oxidative stress markers, cytokine dosage by enzyme-linked immunosorbent assay (ELISA), nuclear factor kappa B (NF-κB) phosphorylation by Western blotting, mRNA expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and neuronal activity by calcium levels were assessed. TC was administered orally 30 min before stimulation with KO₂, and a dose of 30 mg/kg was selected based on previous study. TC inhibited abdominal contortion, mechanical hyperalgesia, paw edema, and myeloperoxidase activity (an indirect marker of macrophage/neutrophil recruitment). TC induced antioxidant activity (assessed by ferric reducing ability and free radical scavenging), while reducing superoxide anion production and lipid peroxidation, at least in part, by upregulating Nrf2 and downregulating Gp91^phox and Cox-2 mRNA expression. TC inhibited KO₂-induced NF-κβ phosphorylation as well as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-33 production. Finally, TC reduced the activation of transient receptor potential vanilloid 1 (TRPV1⁺) and transient receptor potential ankyrin 1 (TRPA1⁺) nociceptive neurons in the dorsal root ganglia. These results demonstrate that the in vivo anti-inflammatory and analgesic activities of TC involve neuronal and non-neuronal mechanisms, and that non-antioxidant flavonoids are still biologically active.