Specialized Pro-Resolving Lipid Mediators: Endogenous Roles and Pharmacological Activities in Infections.

During an infection, inflammation mobilizes immune cells to eliminate the pathogen and protect the host. However, inflammation can be detrimental when exacerbated and/or chronic. The resolution phase of the inflammatory process is actively orchestrated by the specialized pro-resolving lipid mediators (SPMs), generated from omega-3 and -6 polyunsaturated fatty acids (PUFAs) that bind to different G-protein coupled receptors to exert their activity. As immunoresolvents, SPMs regulate the influx of leukocytes to the inflammatory site, reduce cytokine and chemokine levels, promote bacterial clearance, inhibit the export of viral transcripts, enhance efferocytosis, stimulate tissue healing, and lower antibiotic requirements. Metabolomic studies have evaluated SPM levels in patients and animals during infection, and temporal regulation of SPMs seems to be essential to properly coordinate a response against the microorganism. In this review, we summarize the current knowledge on SPM biosynthesis and classifications, endogenous production profiles and their effects in animal models of bacterial, viral and parasitic infections.

Hesperidin Methyl Chalcone Reduces the Arthritis Caused by TiO2 in Mice: Targeting Inflammation, Oxidative Stress, Cytokine Production, and Nociceptor Sensory Neuron Activation.

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 gp91phox, 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.

Hydroethanolic Extract of Grape Peel from Vitis labrusca Winemaking Waste: Antinociceptive and Anti-Inflammatory Activities.

Research background: Extracts from grape pomace, including the wine, show many biological effects such as antioxidant and anti-inflammatory activities. Unfortunately, winemakers discard the bagasse, so the waste is not exploited, although it contains bioactive compounds with antioxidant and anti-inflammatory properties. The work aims to analyze the hydroethanolic extract of peels from Vitis labrusca agro-industrial waste and to evaluate its antinociceptive and anti-inflammatory properties. This study is relevant for reusing a residue and adding value to the grape economic chain. Experimental approach: A representative sample of pomace was obtained and the peels were used to produce the extract. The phenolic compounds were determined by mass spectrometry in multiple reaction monitoring mode and Folin-Ciocalteu colorimetric method, using gallic acid as standard. The biological analyses were carried out using mice orally treated with crude extract at doses of 30, 100 and 300 mg/kg. We evaluated mechanical hyperalgesia by the von Frey method, thermal heat hyperalgesia using a hot plate at 55 °C, paw edema using a pachymeter, and neutrophil recruitment by measurement of myeloperoxidase activity. The nephrotoxicity and hepatotoxicity were evaluated by biochemical analyses using blood samples that were collected after the Vitis labrusca administration. Results and conclusions: In all wet winemaking residues peel mass fraction was 75%, and in dry residues 59%. We identified nine anthocyanins (3-O-glucosides: peonidin, delphinidin, petunidin and malvidin; 3-p-coumaroyl-glucosides: cyanidin, peonidin, petunidin and malvidin, and malvidin-3,5-diglucoside), five flavonoids (apigenin-7-glucoside, luteolin-7-glucoside, quercetin-3-galactoside, isorhamnetin-3-glucoside and myricetin-3-rutinoside), and mass fraction of phenolic compounds, expressed as gallic acid equivalents, was 26.62 mg/g. In vivo assays showed that Vitis labrusca extract at mass fractions 100 and 300 mg/kg reduced carrageenan-induced mechanical and thermal hyperalgesia, 50% of the paw edema, and neutrophil recruitment. In addition, there were no indications of nephrotoxicity and hepatotoxicity. Our extract obtained from winemaking residue has analgesic and anti-inflammatory properties, related at least in part to the presence of phenolic compounds, and it is not toxic to renal and hepatic tissues. Novelty and scientific contribution: This bio-product can be used as an alternative to synthetic anti-inflammatory agents with the same pharmacological potential and fewer side effects. We demonstrated that Vitis labrusca winemaking waste can be used for the production of antinociceptive and anti-inflammatory products (nutraceutical, pharmaceutical and cosmetics) without toxicity, contributing to the environmental economy.

Topical Administration of 15-Deoxy-Δ 12,14-Prostaglandin J2 Using a Nonionic Cream: Effect on UVB-Induced Skin Oxidative, Inflammatory, and Histopathological Modifications in Mice.

UVB radiation is certainly one of the most important environmental threats to which we are subjected to. This fact highlights the crucial protective role of the skin. However, the skin itself may not be capable of protecting against UVB depending on irradiation intensity and time of exposition. Sun blockers are used to protect our skin, but they fail to fully protect it against oxidative and inflammatory injuries initiated by UVB. To solve this issue, topical administration of active molecules is an option. 15-Deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2) is an arachidonic acid-derived lipid with proresolution and anti-inflammatory actions. However, as far as we are aware, there is no evidence of its therapeutic use in a topical formulation to treat the deleterious events initiated by UVB, which was the aim of the present study. We used a nonionic cream to vehiculate 15d-PGJ2 (30, 90, and 300 ng/mouse) (TFcPGJ2) in the skin of hairless mice. UVB increased skin edema, myeloperoxidase activity, metalloproteinase-9 activity, lipid peroxidation, superoxide anion production, gp91phox and COX-2 mRNA expression, cytokine production, sunburn and mast cells, thickening of the epidermis, and collagen degradation. UVB also diminished skin ability to reduce iron and scavenge free radicals, reduced glutathione (GSH), sulfhydryl proteins, and catalase activity. TFcPGJ2 inhibited all these pathological alterations in the skin caused by UVB. No activity was observed with the unloaded topical formulation. The protective outcome of TFcPGJ2 indicates it is a promising therapeutic approach against cutaneous inflammatory and oxidative pathological alterations.

Specialized pro-resolving lipid mediators: A new class of non-immunosuppressive and non-opioid analgesic drugs.

We now appreciate that the mechanism of resolution depends on an active and time-dependent biosynthetic shift from pro-inflammatory to pro-resolution mediators, the so-called specialized pro-resolving lipid mediators (SPMs). These SPMs are biosynthesized from the omega-3 fatty acids arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), or docosahexaenoic acid (DHA). Despite effective for a fraction of patients with rheumatic diseases and neuropathic pain, current analgesic therapies such as biological agents, opioids, corticoids, and gabapentinoids cause unwanted side effects, such as immunosuppression, addiction, or induce analgesic tolerance. A growing body of evidence demonstrates that isolated SPMs show efficacy at very low doses and have been successively used as therapeutic drugs to treat pain and infection in experimental models showing no side effects. Moreover, SPMs work as immunoresolvents and some of them present long-lasting analgesic and anti-inflammatory effects (i.e. block pain without immunosuppressive effects). In this review, we focus on how SPMs block pain, infection and neuro-immune interactions and, therefore, emerge as a new class of non-immunosuppressive and non-opioid analgesic drugs.

IL-33 enhances macrophage release of IL-1ß and promotes pain and inflammation in gouty arthritis.

OBJECTIVE: To investigate the role of IL-33 in gouty arthritis. MATERIAL: 174 Balb/c (wild-type) and 54 ST2-/- mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels. METHODS: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM. RESULTS: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1ß and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1ß and TNF-α, and BMDMs from ST2-/- showed reduced levels of these cytokines after stimulus with MSU crystals. CONCLUSION: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.

Diosmin Treats Lipopolysaccharide-Induced Inflammatory Pain and Peritonitis by Blocking NF-κB Activation in Mice.

Gram-negative bacterial infections induce inflammation and pain. Lipopolysaccharide (LPS) is a pathogen-associated molecular pattern and the major constituent of Gram-negative bacterial cell walls. Diosmin is a citrus flavonoid with antioxidant and anti-inflammatory activities. Here we investigated the efficacy of diosmin in a nonsterile model of inflammatory pain and peritonitis induced by LPS. Diosmin reduced in a dose-dependent manner LPS-induced inflammatory mechanical hyperalgesia, thermal hyperalgesia, and neutrophil recruitment to the paw (myeloperoxidase activity). Diosmin also normalized changes in paw weight distribution assessed by static weight bearing as a nonreflexive method of pain measurement. Moreover, treatment with diosmin inhibited LPS-induced peritonitis as observed by a reduction of leukocyte recruitment and oxidative stress. Diosmin reduced LPS-induced total ROS production (DCFDA assay) and superoxide anion production (NBT assay and NBT-positive cells). We also observed a reduction of LPS-induced oxidative stress and cytokine production (IL-1ß, TNF-α, and IL-6) in the paw. Furthermore, we demonstrated that diosmin inhibited LPS-induced NF-κB activation in peritoneal exudate. Thus, we demonstrated, using a model of nonsterile inflammation induced by LPS, that diosmin is a promising molecule for the treatment of inflammation and pain.

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development.

Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation.

Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1ß, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.

Hesperidin methyl chalcone interacts with NFκB Ser276 and inhibits zymosan-induced joint pain and inflammation, and RAW 264.7 macrophage activation.

Arthritis can be defined as a painful musculoskeletal disorder that affects the joints. Hesperidin methyl chalcone (HMC) is a flavonoid with analgesic, anti-inflammatory, and antioxidant effects. However, its effects on a specific cell type and in the zymosan-induced inflammation are unknown. We aimed at evaluating the effects of HMC in a zymosan-induced arthritis model. A dose-response curve of HMC (10, 30, or 100 mg/kg) was performed to determine the most effective analgesic dose after intra-articular zymosan stimuli. Knee joint oedema was determined using a calliper. Leukocyte recruitment was performed by cell counting on knee joint wash as well as histopathological analysis. Oxidative stress was measured by colorimetric assays (GSH, FRAP, ABTS and NBT) and RT-qPCR (gp91phox and HO-1 mRNA expression) performed. In vitro, oxidative stress was assessed by DCFDA assay using RAW 264.7 macrophages. Cytokine production was evaluated in vivo and in vitro by ELISA. In vitro NF-κB activation was analysed by immunofluorescence. We observed HMC reduced mechanical hypersensitivity and knee joint oedema, leukocyte recruitment, and pro-inflammatory cytokine levels. We also observed a reduction in zymosan-induced oxidative stress as per increase in total antioxidant capacity and reduction in gp91phox and increase in HO-1 mRNA expression. Accordingly, total ROS production and macrophage NFκB activation were diminished. HMC interaction with NFκB p65 at Ser276 was revealed using molecular docking analysis. Thus, data presented in this work suggest the usefulness of HMC as an analgesic and anti-inflammatory in a zymosan-induced arthritis model, possibly by targeting NFκB activation in macrophages.

Contribution of spinal cord glial cells to L. amazonensis experimental infection-induced pain in BALB/c mice.

BACKGROUND: The cellular and molecular pathophysiological mecha\nisms of pain processing in neglected parasitic infections such as leishmaniasis remain unknown. The present study evaluated the participation of spinal cord glial cells in the pathophysiology of pain induced by Leishmania amazonensis infection in BALB/c mice. METHODS: Mice received intra-plantar (i.pl.) injection of L. amazonensis (1 × 105) and hyperalgesia, and paw edema were evaluated bilaterally for 40 days. The levels of TNF-α and IL-1ß, MPO activity, and histopathology were assessed on the 40th day. ATF3 mRNA expression was assessed in DRG cells at the 30th day post-infection. Blood TNF-α and IL-1ß levels and systemic parasite burden were evaluated 5-40 days after the infection. At the 30th day post-infection L. amazonensis, the effects of intrathecal (i.t.) treatments with neutralizing antibody anti-CX3CL1, etanercept (soluble TNFR2 receptor), and interleukin-1 receptor antagonist (IL-1ra) on infection-induced hyperalgesia and paw edema were assessed. In another set of experiments, we performed a time course analysis of spinal cord GFAP and Iba-1 (astrocytes and microglia markers, respectively) and used confocal immunofluorescence and Western blot to confirm the expression at the protein level. Selective astrocyte (α-aminoadipate) and microglia (minocycline) inhibitors were injected i.t. to determine the contribution of these cells to hyperalgesia and paw edema. The effects of i.t. treatments with glial and NFκB (PDTC) inhibitors on spinal glial activation, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation were also evaluated. Finally, the contribution of TNF-α and IL-1ß to CX3CL1 mRNA expression was investigated. RESULTS: L. amazonensis infection induced chronic mechanical and thermal hyperalgesia and paw edema in the infected paw. Mechanical hyperalgesia was also observed in the contralateral paw. TNF-α, IL-1ß, MPO activity, and epidermal/dermal thickness increased in the infected paw, which confirmed the peripheral inflammation at the primary foci of this infection. ATF3 mRNA expression at the ipsilateral DRG of the infected paw was unaltered 30 days post-infection. TNF-α and IL-1ß blood levels were not changed over the time course of disease, and parasitism increased in a time-dependent manner in the ipsilateral draining lymph node. Treatments targeting CX3CL1, TNF-α, and IL-1ß inhibited L. amazonensis-induced ongoing mechanical and thermal hyperalgesia, but not paw edema. A time course of GFAP, Iba-1, and CX3CR1 mRNA expression indicated spinal activation of astrocytes and microglia, which was confirmed at the GFAP and Iba-1 protein level at the peak of mRNA expression (30th day). Selective astrocyte and microglia inhibition diminished infection-induced ipsilateral mechanical hyperalgesia and thermal hyperalgesia, and contralateral mechanical hyperalgesia, but not ipsilateral paw edema. Targeting astrocytes, microglia and NFκB diminished L. amazonensis-induced GFAP, Iba-1, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation in the spinal cord at the peak of spinal cord glial cells activation. CX3CL1 mRNA expression was also detected in the ipsilateral DRG of infected mice at the 30th day post-infection, and the i.t. injection of TNF-α or IL-1ß in naïve animals induced CX3CL1 mRNA expression in the spinal cord and ipsilateral DRG. CONCLUSIONS: L. amazonensis skin infection produces chronic pain by central mechanisms involving spinal cord astrocytes and microglia-related production of cytokines and chemokines, and NFκB activation contributes to L. amazonensis infection-induced hyperalgesia and neuroinflammation.

Repurposing of the Nootropic Drug Vinpocetine as an Analgesic and Anti-Inflammatory Agent: Evidence in a Mouse Model of Superoxide Anion-Triggered Inflammation.

Clinically active drugs for the treatment of acute pain have their prescription limited due to the significant side effects they induce. An increase in reactive oxygen species (ROS) has been linked to several conditions, including inflammation and pain processing. Therefore, new or repurposed drugs with the ability of reducing ROS-triggered responses are promising candidates for analgesic drugs. Vinpocetine is a clinically used nootropic drug with antioxidant, anti-inflammatory, and analgesic properties. However, the effects of vinpocetine have not been investigated in a model with a direct relationship between ROS, inflammation, and pain. Based on that, we aimed to investigate the effects of vinpocetine in a model of superoxide anion-induced pain and inflammation using potassium superoxide (KO2) as a superoxide anion donor to trigger inflammation and pain. In the KO2 model, vinpocetine dose-dependently reduced pain-like behaviors (spontaneous pain and hyperalgesia), paw edema, and neutrophil and mononuclear cell recruitment to the paw skin (assessed by H&E staining, fluorescence, and enzymatic assays) and to the peritoneal cavity. Vinpocetine also restored tissue endogenous antioxidant ability and Nrf2 and Ho-1 mRNA expression and reduced superoxide anion production and gp91phox mRNA expression. We also observed the inhibition of IκBα degradation by vinpocetine, which demonstrates a reduction in the activation of NF-κB explaining the diminished production of IL-33, IL-1ß, and TNF-α. Collectively, our data show that vinpocetine alleviates pain and inflammation induced by KO2, which is a mouse model with a direct role of ROS in triggering pain and other inflammatory phenomena. Thus, the results suggest the repurposing of vinpocetine as an anti-inflammatory and analgesic drug.

The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin.

Rutin is a glycone form of the flavonol quercetin and it reduces inflammatory pain in animal models. Therapy with granulocyte colony-stimulating factor (G-CSF) is known by the pain caused as its main side effect. The effect of rutin and its mechanisms of action were evaluated in a model of hyperalgesia induced by G-CSF in mice. The mechanical hyperalgesia induced by G-CSF was reduced by treatment with rutin in a dose-dependent manner. Treatment with both rutin + morphine or rutin + indomethacin, at doses that are ineffectual per se, significantly reduced the pain caused by G-CSF. The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-ATP-sensitive potassium channel (KATP) signaling pathway activation is one of the analgesic mechanisms of rutin. Rutin also reduced the pro-hyperalgesic and increased anti-hyperalgesic cytokine production induced by G-CSF. Furthermore, rutin inhibited the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NFκB), which might explain the inhibition of the cytokine production. Treatment with rutin upregulated the decreased mRNA expression of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) combined with enhancement of the mRNA expression of the Nrf2 downstream target heme oxygenase (HO-1). Intraperitoneal (i.p.) treatment with rutin did not alter the mobilization of neutrophils induced by G-CSF. The analgesia by rutin can be explained by: NO-cGMP-PKG-KATP channel signaling activation, inhibition of NFκB and triggering the Nrf2/HO-1 pathway. The present study demonstrates rutin as a promising pharmacological approach to treat the pain induced by G-CSF without impairing its primary therapeutic benefit of mobilizing hematopoietic progenitor cells into the blood.

The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells.

BACKGROUND: Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. METHODS: The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7-150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. RESULTS: Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1ß mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). CONCLUSIONS: Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.

Naringenin mitigates titanium dioxide (TiO2)-induced chronic arthritis in mice: role of oxidative stress, cytokines, and NFκB.

OBJECTIVE: To evaluate the effect and mechanisms of naringenin in TiO2-induced chronic arthritis in mice, a model resembling prosthesis and implant inflammation. TREATMENT: Flavonoids are antioxidant and anti-inflammatory molecules with important anti-inflammatory effect. Mice were daily treated with the flavonoid naringenin (16.7-150 mg/kg, orally) for 30 days starting 24 h after intra-articular knee injection of 3 mg of TiO2. METHODS: TiO2-induced arthritis resembles cases of aseptic inflammation induced by prosthesis and/or implants. Mice were stimulated with 3 mg of TiO2 and after 24 h mice started to be treated with naringenin. The disease phenotype, treatment toxicity, histopathological damage, oxidative stress, cytokine expression and NFκB were evaluated after 30 days of treatment. RESULTS: Naringenin inhibited TiO2-induced mechanical hyperalgesia (96%), edema (77%) and leukocyte recruitment (74%) without inducing toxicity. Naringenin inhibited histopathological index (HE, 49%), cartilage damage (Toluidine blue tibial staining 49%, and proteoglycan 98%), and bone resorption (TRAP-stained 73%). These effects were accompanied by inhibition of oxidative stress (gp91phox 93%, NBT 83%, and TBARS 41%) cytokine mRNA expression (IL-33 82%, TNFα 76%, pro-IL-1ß 100%, and IL-6 61%), and NFκB activation (100%). CONCLUSION: Naringenin ameliorates TiO2-induced chronic arthritis inducing analgesic and anti-inflammatory responses with improvement in the histopathological index, cartilage damage, and bone resorption.

Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice.

Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI.

trans-Chalcone, a flavonoid precursor, inhibits UV-induced skin inflammation and oxidative stress in mice by targeting NADPH oxidase and cytokine production.

trans-Chalcone is a plant flavonoid precursor, which lacks broad investigation on its biological activity in inflammatory processes. In the present study, anti-inflammatory and antioxidant mechanisms of systemic administration with trans-chalcone, a flavonoid precursor, on ultraviolet (UV) irradiation-induced skin inflammation and oxidative stress in hairless mice were investigated by the following parameters: skin edema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR and cytokine production by ELISA. Systemic treatment with trans-chalcone inhibited skin inflammation by reducing skin edema and neutrophil recruitment, and also inhibited matrix metalloproteinase-9 activity. trans-Chalcone also inhibited oxidative stress, gp91phox mRNA expression, and the production of a wide range of pro-inflammatory cytokines, while it did not affect anti-inflammatory cytokines induced by UV irradiation. However, trans-chalcone did not prevent oxidative stress in vitro, suggesting that its in vivo effect is more related to anti-inflammatory properties rather than a direct antioxidant effect. In conclusion, treatment with trans-chalcone inhibited UV-induced skin inflammation resulting in oxidative stress inhibition in vivo. Therefore, systemic supplementation with this compound may represent an important therapeutic approach in inflammatory skin diseases induced by UV irradiation.

Leishmania infection: painful or painless?

The complex life cycle and immunopathological features underpinning the interaction of Leishmania parasites and their mammalian hosts poses frequent poorly explored and inconclusively resolved questions. The altered nociceptive signals over the course of leishmaniasis remain an intriguing issue for nociceptive and parasitology researchers. Experimental investigations have utilized behavioral, morphological, and neuro-immune approaches in the study of experimental cutaneous leishmaniasis (CL). The data generated indicates new venues for the study of the pathological characteristics of nociceptive processing in this parasitic disease. Leishmania-induced pain may be easily observed in mice and rats. However, nociceptive data is more complex in human investigations, including the occurrence of painless lesions in mucocutaneous and cutaneous leishmaniasis. Data from recent decades indicate that humans can also be affected by pain-related symptoms, often distinct from the region of body infection. The molecular and cellular mechanisms underlying such variable nociceptive states in humans during the course of leishmaniasis are an active area of research. The present article reviews nociception in leishmaniasis, including in experimental models of CL and clinical reports.

Neutrophils and arthritis: Role in disease and pharmacological perspectives.

The inflammatory response in the joint can induce an intense accumulation of leukocytes in the tissue that frequently results in severe local damage and loss of function. Neutrophils are essential cells to combat many pathogens, but their arsenal can contribute or aggravate articular inflammation. Here we summarized some aspects of neutrophil biology, their role in inflammation and indicated how the modulation of neutrophil functions could be useful for the treatment of different forms of arthritis.

Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses.

In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders.