Annexin A1 Mimetic Peptide and Piperlongumine: Anti-Inflammatory Profiles in Endotoxin-Induced Uveitis.

Uveitis is one of the main causes of blindness worldwide, and therapeutic alternatives are worthy of study. We investigated the effects of piperlongumine (PL) and/or annexin A1 (AnxA1) mimetic peptide Ac2-26 on endotoxin-induced uveitis (EIU). Rats were inoculated with lipopolysaccharide (LPS) and intraperitoneally treated with Ac2-26 (200 µg), PL (200 and 400 µg), or Ac2-26 + PL after 15 min. Then, 24 h after LPS inoculation, leukocytes in aqueous humor, mononuclear cells, AnxA1, formyl peptide receptor (fpr)1, fpr2, and cyclooxygenase (COX)-2 were evaluated in the ocular tissues, along with inflammatory mediators in the blood and macerated supernatant. Decreased leukocyte influx, levels of inflammatory mediators, and COX-2 expression confirmed the anti-inflammatory actions of the peptide and pointed to the protective effects of PL at higher dosage. However, when PL and Ac2-26 were administered in combination, the inflammatory potential was lost. AnxA1 expression was elevated among groups treated with PL or Ac2-26 + PL but reduced after treatment with Ac2-26. Fpr2 expression was increased only in untreated EIU and Ac2-26 groups. The interaction between Ac2-26 and PL negatively affected the anti-inflammatory action of Ac2-26 or PL. We emphasize that the anti-inflammatory effects of PL can be used as a therapeutic strategy to protect against uveitis.

Protective effects of piperlongumin in the prevention of inflammatory damage caused by pulmonary exposure to benzopyrene carcinogen.

Benzopyrene is one of the main polycyclic aromatic hydrocarbons with carcinogenic capacity. Research has shown that anti-inflammatory drugs can reduce the incidence of lung cancer. In this scenario, we highlight piperlongumin (PL), an alkaloid from Piper longum with anti-inflammatory properties. Therefore, our aim was to study the effect of PL administration in a model of pulmonary carcinogenesis induced by benzopyrene in Balb/c mice. Animals were divided into 3 groups (n = 10/group): sham (10% DMSO), induced by benzopyrene (100 mg/kg, diluted in DMSO) without treatment (BaP) for 12 weeks and induced by benzopyrene and treated with PL (BaP/PL) (2 mg/kg in 10% DMSO) from the eighth week post-induction. Animals were weighed daily and pletsmography was performed in the 12th week. Genotoxicity and hemoglobin levels were analyzed in blood and quantification of leukocytes in bronchoalveolar lavage (BAL). Lungs were collected for histopathological evaluation, immunohistochemical studies of annexin A1 (AnxA1), cyclooxygenase 2 (COX-2), anti-apoptotic protein Bcl-2 and nuclear transcription factor (NF-kB) and also the measurement of interleukin cytokines (IL)-1ß, IL-17 and tumor necrosis factor (TNF) -α. Treatment with PL reduced the pulmonary parameters (p < 0,001) of frequency, volume and pulmonary ventilation, decreased lymphocytes, monocytes and neutrophils in BAL (p < 0,05) as well as blood hemoglobin levels (p < 0,01). PL administration also reduced DNA damage and preserved the pulmonary architecture compared to the BaP group. Moreover, the anti-inflammatory effect of PL was evidenced by the maintenance of AnxA1 levels, reduction of COX-2 (p < 0,05), Bcl-2 (p < 0,01) and NF-kB (p < 0,001) expressions and decreased IL-1ß, IL-17 (p < 0,01) and TNF-α (p < 0,05) levels. The results show the therapeutic potential of PL in the treatment of pulmonary anti-inflammatory and anti-tumor diseases with promising therapeutic implications.

Expression of the Annexin A1 and its correlation with matrix metalloproteinases and the receptor for formylated peptide-2 in diffuse astrocytic tumors.

Astrocytomas represent the majority of cerebral gliomas. Studies show that the anti-inflammatory protein Annexin-A1 (ANXA1) is associated with the tumor invasion process and that its actions can be mediated by the receptor for formylated peptides (FPR). Therefore, we evaluated the expression of ANXA1, the receptor FPR2 and matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in brain astrocytomas. Detection of proteins was performed in sections of diffuse astrocytomas (grade II), anaplastic astrocytomas (grade III) and glioblastomas (GBM, grade IV) and quantifications were made by densitometry. Our analyses showed increased expression of ANXA1 in astrocytomas of all grades, but especially in GBM. The expression of FPR2 is similar to that found for ANXA1, being higher in GBM. Immunostaining for MMPs is also stronger as the degree of malignancy increases, especially with respect to MMP-9. The positive correlation between ANXA1/FPR2 and ANXA1/MMP-9 was observed in all tumors studied. The data indicate the possible action of ANXA1 and FPR2 on the development and progression of astrocytomas, related to increased expression of MMP-9. Thereby, ANXA1 and FPR2 are involved in the biology and malignancy of diffuse astrocytic tumors.

Anti-inflammatory actions of herbal medicines in a model of chronic obstructive pulmonary disease induced by cigarette smoke.

The effects of four medicinal herbs (Arctium lappa, Plantago major, Mikania glomerata Spreng and Equisetum arvense) with anti-inflammatory properties were evaluated in a chronic obstructive pulmonary disease (COPD) model. Wistar rats were exposed to cigarette smoke during 8 weeks and one of the groups was orally given a solution containing 4% of each alcoholic herbal extracts during the exposure period. Control group was not exposed to smoke or treated. Histopathological, immunohistochemical and biochemical analyzes were performed. Normal blood plasma levels of gamma glutamyl transferase indicated no toxicity of the administered herbal extracts. The treatment reduced leukocytes influx in bronchoalveolar lavage, mast cell and macrophages numbers in lungs, as well as prevented pulmonary congestion and tracheal metaplasia. Herbal mixture also decreased plasma inflammatory mediator levels and pulmonary expression of annexin A1 and nuclear factor-k?. Our data indicate synergistic and protective effects of the used herbal medicines in animals exposed to cigarette smoke as a potential therapeutic strategy.