Victor Fattori

Quercetin-Loaded Microcapsules Ameliorate Experimental Colitis in Mice by Anti-inflammatory and Antioxidant Mechanisms

Quercetin (1) is an anti-inflammatory and antioxidant flavonoid. However, the oral administration of 1 did not lead to beneficial effects in experimental animal colitis models, which involve cytokines and oxidative stress. A possible explanation is that the absorption profile of 1 prevents its activity. Therefore, it was reasoned that the controlled release of 1 would improve its therapeutic effect. Thus, the therapeutic effect and mechanisms of 1-loaded microcapsules in acetic acid-induced colitis in mice were evaluated. Microcapsules were prepared using pectin/casein polymer and 1. The oral administration of 1-loaded microcapsules decreased neutrophil recruitment, attenuated histological alterations, and reduced macroscopical damage, edema, and IL-1β and IL-33 production in the colon samples. Microcapsules loaded with 1 also prevented the reduction of anti-inflammatory cytokine IL-10 and the antioxidant capacity of the colon. These preclinical data indicate that pectin/casein polymer microcapsules loaded with 1 improved the anti-inflammatory and antioxidant effects of 1 compared to the nonencapsulated drug. Therefore, quercetin seems to be a promising active molecule in inflammatory bowel disease if provided with adequate controlled release.

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.

Quercetin Reduces Neutrophil Recruitment Induced by CXCL8, LTB4, and fMLP: Inhibition of Actin Polymerization

Recent in vitro data have suggested that the flavonoid quercetin (1) does not affect the functioning of neutrophils. Therefore, we evaluated in vivo and in vitro whether or not 1 affects neutrophil function, focusing on recruitment. The in vivo treatment with 1 inhibited in a dose-dependent manner the recruitment of neutrophils to the peritoneal cavity of mice induced by known chemotatic factors such as CXCL1, CXCL5, LTB(4), and fMLP. Furthermore, 1 also inhibited in a concentration-dependent manner the chemoattraction of human neutrophils induced by CXCL8, LTB(4), and fMLP in a Boyden chamber. In vitro treatment with 1 did not affect human neutrophil surface expression of CXCR1, CXCR2, BLT1, or FLPR1, but rather reduced actin polymerization. These results suggest that 1 inhibits actin polymerization, hence, explaining the inhibition of neutrophil recruitment in vivo and in vitro and highlighting its possible usefulness to diminish excessive neutrophil migration during inflammation.

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.

Vanillic Acid Inhibits Inflammatory Pain by Inhibiting Neutrophil Recruitment, Oxidative Stress, Cytokine Production, and NFκB Activation in Mice

Vanillic acid (1) is a flavoring agent found in edible plants and fruits. It is an oxidized form of vanillin. Phenolic compounds form a substantial part of plant foods used as antioxidants with beneficial biological activities. These compounds have received considerable attention because of their role in preventing human diseases. Especially, 1 presents antibacterial, antimicrobial, and chemopreventive effects. However, the mechanisms by which 1 exerts its anti-inflammatory effects in vivo are incompletely understood. Thus, the effect of 1 was evaluated in murine models of inflammatory pain. Treatment with 1 inhibited the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, the second phase of the formalin test, and complete Freunds adjuvant (CFA). Treatment with 1 also inhibited carrageenan- and CFA-induced mechanical hyperalgesia, paw edema, myeloperoxidase activity, and N-acetyl-β-D-glucosaminidase activity. The anti-inflammatory mechanisms of 1 involved the inhibition of oxidative stress, pro-inflammatory cytokine production, and NFκB activation in the carrageenan model. The present study demonstrated 1 presents analgesic and anti-inflammatory effects in a wide range of murine inflammation models, and its mechanisms of action involves antioxidant effects and NFκB-related inhibition of pro-inflammatory cytokine production.

Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice

Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNFα actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1(-/-) mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation.

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

&NA; 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 24 h 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‐&kgr;B 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‐&kgr;B activation. To our knowledge, this is the first study demonstrating that diclofenac‐induced AKI increases NF‐&kgr;B activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac‐induced AKI. Graphical abstract Figure. No caption available.

Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress.

Hypericum perforatum is a medicinal plant with anti‐inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)‐induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15–3.0 g/kg, p.o.) induced dose‐dependent mortality. The sub‐maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30–300 mg/kg, i.p.) dose‐dependently reduced paracetamol‐induced lethality. Paracetamol‐induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL‐1β, TNF‐α, and IFN‐γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2′‐azinobis‐(3‐ethylbenzothiazoline‐6‐sulfonate radical cation; ABTS˙+) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol‐induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol‐induced cytokine production, neutrophil recruitment, and oxidative stress. Copyright

Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress

We evaluated the effect of pyrrolidine dithiocarbamate (PDTC) in superoxide anion-induced inflammatory pain. Male Swiss mice were treated with PDTC and stimulated with an intraplantar or intraperitoneal injection of potassium superoxide, a superoxide anion donor. Subcutaneous PDTC treatment attenuated mechanical hyperalgesia, thermal hyperalgesia, paw oedema and leukocyte recruitment (neutrophils and macrophages). Intraplantar injection of superoxide anion activated NF-κB and increased cytokine production (IL-1β, TNF-α and IL-10) and oxidative stress (nitrite and lipid peroxidation levels) at the primary inflammatory foci and in the spinal cord (L4–L6). PDTC treatment inhibited superoxide anion-induced NF-κB activation, cytokine production and oxidative stress in the paw and spinal cord. Furthermore, intrathecal administration of PDTC successfully inhibited superoxide anion-induced mechanical hyperalgesia, thermal hyperalgesia and inflammatory response in peripheral foci (paw). These results suggest that peripheral stimulus with superoxide anion activates the local and spinal cord oxidative- and NF-κB-dependent inflammatory nociceptive mechanisms. PDTC targets these events, therefore, inhibiting superoxide anion-induced inflammatory pain in mice.

Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice.

The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise.