Jefferson Crespigio

5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

5-Lipoxygenase (5-LO) converts arachidonic acid into leukotrienes (LTs) and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP)-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO−/−) mice and background wild type mice were challenged with APAP (0.3–6 g/kg) or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO−/− mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10), superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate) assay were prevented in 5-LO−/− mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

Genetic aspects of adrenocortical tumours and hyperplasias

Adrenocortical tumours (ACT), which include adenomas, carcinomas and adrenal hyperplasia, may be associated with genetic syndromes, such as Li–Fraumeni syndrome, Beckwith–Wiedemann syndrome, multiple endocrine neoplasia type 1, familial adenomatous polyposis and Carney complex. Genetic defects have been found to be responsible for the disease in most of these syndromes, allowing genetic counselling to affected patients and family members. Here, we summarize the clinical criteria of these hereditary syndromes and briefly describe the genetic alterations related to them. In addition, we discuss the involvement of various genetic defects in the development of sporadic adrenocortical tumours.

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.

Quercetin Reduces Ehrlich Tumor-Induced Cancer Pain in Mice

Cancer pain directly affects the patients quality of life. We have previously demonstrated that the subcutaneous administration of the mammary adenocarcinoma known as Ehrlich tumor induces pain in mice. Several studies have shown that the flavonoid quercetin presents important biological effects, including anti-inflammatory, antioxidant, analgesic, and antitumor activity. Therefore, the analgesic effect and mechanisms of quercetin were evaluated in Ehrlich tumor-induced cancer pain in mice. Intraperitoneal (i.p.) treatments with quercetin reduced Ehrlich tumor-induced mechanical and thermal hyperalgesia, but not paw thickness or histological alterations, indicating an analgesic effect without affecting tumor growth. Regarding the analgesic mechanisms of quercetin, it inhibited the production of hyperalgesic cytokines IL-1β and TNFα and decreased neutrophil recruitment (myeloperoxidase activity) and oxidative stress. Naloxone (opioid receptor antagonist) inhibited quercetin analgesia without interfering with neutrophil recruitment, cytokine production, and oxidative stress. Importantly, cotreatment with morphine and quercetin at doses that were ineffective as single treatment reduced the nociceptive responses. Concluding, quercetin reduces the Ehrlich tumor-induced cancer pain by reducing the production of hyperalgesic cytokines, neutrophil recruitment, and oxidative stress as well as by activating an opioid-dependent analgesic pathway and potentiation of morphine analgesia. Thus, quercetin treatment seems a suitable therapeutic approach for cancer pain that merits further investigation.

The Ehrlich Tumor Induces Pain-Like Behavior in Mice: A Novel Model of Cancer Pain for Pathophysiological Studies and Pharmacological Screening

The Ehrlich tumor is a mammary adenocarcinoma of mice that can be developed in solid and ascitic forms depending on its administration in tissues or cavities, respectively. The present study investigates whether the subcutaneous plantar administration of the Ehrlich tumor cells induces pain-like behavior and initial pharmacological susceptibility characteristics. The Ehrlich tumor cells (1 × 104–107 cells) induced dose-dependent mechanical hyperalgesia (electronic version of the von Frey filaments), paw edema/tumor growth (caliper), and flinches compared with the saline group between days 2 and 12. There was no difference between doses of cells regarding thermal hyperalgesia in the hot-plate test. Indomethacin (a cyclooxygenase inhibitor) and amitriptyline hydrochloride (a tricyclic antidepressant) treatments did not affect flinches or thermal and mechanical hyperalgesia. On the other hand, morphine (an opioid) inhibited the flinch behavior and the thermal and mechanical hyperalgesia. These effects of morphine on pain-like behavior were prevented by naloxone (an opioid receptor antagonist) treatment. None of the treatments affected paw edema/tumor growth. The results showed that, in addition to tumor growth, administration of the Ehrlich tumor cells may represent a novel model for the study of cancer pain, specially the pain that is susceptible to treatment with opioids, but not to cyclooxygenase inhibitor or to tricyclic antidepressant.

The flavonoid quercetin inhibits titanium dioxide (TiO2)-induced chronic arthritis in mice

Titanium dioxide (TiO2) is a common component of orthopedic prosthesis. However, prosthesis wear releases TiO2, which induces inflammation and osteolysis in peri-prosthetic tissues. Quercetin is a flavonoid widely present in human diet, which presents biological activities such as antinociceptive, anti-inflammatory and antioxidant effects. Therefore, the effect of intraperitoneal treatment with quercetin in TiO2-induced arthritis model was evaluated. In the first set of experiments, mice received injection of TiO2 (0.1-3 mg/knee joint) and articular mechanical hyperalgesia, edema and histopathology analysis were performed in a 30 days protocol. The dose of 3 mg of TiO2 showed the most harmful effect, and was chosen to the following experiments. Subsequently, mice received 3 mg of TiO2 followed by post-treatment with quercetin during 30 days. Quercetin (10-100 mg/kg) inhibited in a dose-dependent manner TiO2-induced knee joint mechanical hyperalgesia, edema and leukocyte recruitment and did not induce damage in major organs such as liver, kidney and stomach. The dose of 30 mg/kg was chosen for the subsequent analysis, and reduced histopathological changes such as leukocyte infiltration, vascular proliferation and synovial hyperplasia (pannus formation) on day 30 after TiO2 challenge. The protective analgesic and anti-inflammatory mechanisms of quercetin included the inhibition of TiO2-induced neutrophil and macrophage recruitment, proteoglycan degradation, oxidative stress, cytokine production (TNF-α, IL-1β, IL-6, and IL-10), COX-2 mRNA expression, and bone resorption as well as activation of Nrf2/HO-1 signaling pathway. These results demonstrate the potential therapeutic applicability of the dietary flavonoid quercetin to reduce pain and inflammatory damages associated with prosthesis wear process-induced arthritis.

Ectopic hidradenoma papilliferum

Dear Editor, We report a case of a 36-year-old male patient with a two-month history of an asymptomatic, erythematous, 1 x 1cm papule of fibroelastic consistency on the left areola (Figure 1). The left axillary lymph nodes were not enlarged. We performed an excisional biopsy of the papule for diagnosis. Histopathology revealed a dermal tumor with no connection to the overlying epidermis. The lesion contained cells with papillary folds, tubules, cystically dilated spaces, and lumen lined by columnar cells with decapitation secretion, compatible with hidradenoma papilliferum (HP) (Figures 2 and 3). HP is a rare, benign, adnexal tumor that occurs almost exclusively in the anogenital region of female patients.1-4 HP appears as solitary, asymptomatic, well-circumscribed, skin-colored or reddish-brown nodules measuring from 0.5 to 1cm. HP lesions that are not located in the anogenital area are referred to as ectopic HP. 1,4,5 Many cases of HP have been reported since it was first described by Werth in 1878.5 However, very few cases of ectopic HP have been reported in male patients.4 Ectopic HP can occur on the eyelids, orbit, nose, breast, chest, abdomen, and scalp. 4, 5 The histogenesis for both anogenital and ectopic HP remains unclear. Although the presence of human papillomavirus (HPV) DNA has been identified in a few cases, it does not seem to play a role in the pathogenesis of HP. Histopathological findings show dermal tumors with no connection to the overlying epidermis, with papillary and tubular formations, cystically dilated spaces, and lumen lined by columnar cells with decapitation secretion. Such histopathology A

Naringenin Eye Drops Inhibit Corneal Neovascularization by Anti-Inflammatory and Antioxidant Mechanisms

Purpose To investigate the effect of naringenin eye drops in corneal neovascularization induced by alkali (1 N NaOH) burn in mice. Methods Corneal neovascularization in the right eye of male Swiss mice was induced by alkali. Treatment with naringenin eye drops (0.08-80 μg; 8 μL of 0.01-10 g/L solution) or vehicle (saline) started 2 days before corneal neovascularization was induced and was performed twice a day. Mice were treated up until the time animals were euthanized and cornea tissue was collected for testing, which was 2, 4, and 6 hours after alkali stimulus for cytokine and antioxidant capacity measurements, and 3 and/or 7 days after alkali stimulus for the assessment of corneal epithelial thickness and neovascularization, neutrophil, and macrophage recruitment, and vascular endothelial growth factor (Vegf), platelet-derived growth factor (Pdgf), matrix metalloproteinase-14 (Mmp14), and pigment epithelium-derived factor (Pedf) mRNA expression. Results Naringenin eye drops inhibited alkali burn-induced neutrophil (myeloperoxidase activity and recruitment of Lysm-GFP+ cells) and macrophage (N-acetyl-β-D glucosaminidase activity) recruitment into the eye, decrease in epithelial thickness, and neovascularization in the cornea. Further, naringenin inhibited alkali-induced cytokine (IL-1β and IL-6) production, Vegf, Pdgf, and Mmp14 mRNA expression, and the reduction of ferric reducing antioxidant power and Azinobis-(3-Ethylbenzothiazoline 6-Sulfonic acid) radical scavenging capacity as well as increased the reduced glutathione and protein-bound sulfhydryl groups levels. Conclusions Collectively, these results indicate that naringenin eye drops are protective in alkali-induced corneal burn by inhibiting leukocyte recruitment, the proangiogenic factor expression, inflammatory cytokine production, and loss of antioxidant defenses.

Giant cell tumors of the tendon sheath in the left hallux

Dear Editor, This is a case report of a male patient, 47 years of age, with a one-year history of an asymptomatic nodular mass on the left hallux. The patient reported gradual growth, with a rapid increase in size over the past two months. The dermatological examination revealed a firm, painless mass, measuring approximately 5 x 4 cm, on the left hallux (Figures 1A and 1B). The radiographic examination showed no cortical erosion. Microscopic examination revealed a lesion predominantly consisting of mononuclear cells and multinucleated giant cells, dispersed in hyalinized collagen fiber bundles. These findings are compatible with giant cell tumors of the tendon sheath (Figures 2 and 3). The patient underwent tumor wide excision performed by the orthopedist. Giant cell tumors of the tendon sheath (GCT-TS) are solitary benign tumors that represent the second most common tumor on the hand, after ganglion cysts. However, this type of lesion is rare on the foot. Chassaignac was the first to describe these benign masses in 1852 and referred to them as tendon sheath cancer. Jaffe was the first, in 1941, to describe GCT-TS as tenosynovitis, a non-neoplastic malignant reaction.1 Etiopathogenesis of GCT-TS is unknown, but some authors suggest that this disease results from alterations in lipid metabolism, inflammation or other benign neoplastic processes. The possibility of this disease being caused by trauma has been reported in prior literature. 1-4