aloperine and Inflammation

Alveolar epithelial cell death, inflammation, and oxidative stress are typical features of acute lung injury (ALI). Aloperine (Alo), an alkaloid isolated from Sophora alopecuroides, has been reported to display various biological effects, such as anti-inflammatory, immunoregulatory, and anti-oxidant properties. In this study, we investigated the effects and mechanisms of Alo in treating a lipopolysaccharide (LPS)-induced ALI in a murine model.. The effects of Alo in LPS-induced ALI were investigated in C57BL/6 mice. The RIPK1 inhibitor (Nec-1) and the RIPK3 inhibitor (GSK'872) were used to evaluate the relationship of necroptosis, NF-κB activation, and PDC subunits in LPS-treated mouse alveolar epithelial cells (MLE-12). Then the effects of Alo on necroptosis, inflammation, and oxidative stress of LPS-stimulated MLE-12 cells were evaluated.. Alo significantly attenuated histopathological lung injuries and reduced lung wet/dry ratio in LPS-induced ALI mice. Alo also remarkedly reduced total protein and neutrophils recruitment in bronchoalveolar lavage fluid of ALI mice. Meanwhile, Alo ameliorated the LPS-induced necroptosis in the lungs of ALI mice. The RIPK3 inhibitor GSK'872, but not the RIPK1 inhibitor Nec-1, reversed LPS-induced p65 phosphorylation and translocation to the nucleus in MLE-12 cells. GSK'872 also reversed the LPS-induced increase in ROS and binding of RIPK3 and PDC subunits in MLE-12 cells. Moreover, Alo down-regulated the levels of p-RIPK1, p-RIPK3, p-MLKL, p-p65, the translocation of p65 to the nucleus, and reduced the expression of IL-6 and IL-8 in LPS-stimulated MLE-12 cells. Alo also inhibited the binding of RIPK3 and PDC-E1α, PDC-E1β, PDC-E2, and PDC-E3 and the ROS production in LPS-treated MLE-12 cells.. The present study validated the beneficial effects of Alo on LPS-induced ALI , suggesting Alo may be a new drug candidate against ALI.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Inflammation; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Necroptosis; NF-kappa B; Oxidative Stress; Piperidines; Quinolizidines; Reactive Oxygen Species

To explore the effects of aloperine (ALO) on allergic airway inflammation, we investigated whether its mechanism is related with NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. Histochemical staining and inflammatory cell count were used to observe lung histopathological changes in mice. ELISA was used to detect the content of inflammatory cytokines and IgE in the mouse bronchoalveolar lavage fluid (BALF). Airway hyperresponsiveness (AHR) to inhale methacholine was measured by the plethysmography in conscious mice. Immunohistochemical method was used to detect the expression levels of Nrf2 and HO-1 in lung tissues. The key proteins of MAPK, NF-κB, and Nrf2/HO-1 in lung tissues were quantitatively analyzed by Western blot. Finally, the in vitro effect of ALO on the production of pro-inflammatory mediators and cytokines by lipopolysaccharide-stimulated RAW 264.7 cells was also evaluated. In the ovalbumin (OVA)-induced asthma mouse model, ALO reduced the exudation and infiltration of inflammatory cells and suppressed goblet cell hyperplasia. ALO-treated asthmatic mice also decreased the protein levels of interleukin (IL)-4, IL-5, IL-13, IFN-γ, and IgE in BALF and attenuated AHR. Furthermore, ALO inhibited the expression of key proteins of MAPK and NF-κB pathways, and increased the expression of Nrf2/HO-1 in OVA-challenged mice. Additional in vitro study has shown that ALO abrogates the macrophage production of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, IL-6, and IL-1β. Taken together, ALO attenuated allergic airway inflammation through regulating NF-κB, MAPK, and Nrf2/HO-1 signaling pathways. The results suggest the utility of ALO as an anti-inflammatory agent for the treatment of asthma.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Heme Oxygenase-1; Humans; Hypersensitivity; Inflammation; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Piperidines; Quinolizidines; Respiratory System; Signal Transduction

Aloperine, an alkaloid isolated from Sophora alopecuroides L, showed a marked suppressive effect on the swelling of the rat's hind paw induced by injecting carrageenin, macostatin, PGE2, histamine, 5-HT, on the rat's scald oedema induced by scalding its hind paw, and on the increased permeability of capillaries caused by histamine and the leukocytic migratory response. The swelling induced by injecting carrageenin into the hind paw of adrenolectomized rats was still significantly inhibited. Noticeably, aloperine reduced the content of PGE and histamine in the exudate formed after injecting carrageenin and dextran into the rat's hind paw, and increased the stability of red cell membranes, the activity of catalase (CAT) in hepatic tissue of mice, and reduced the content of malondialdehyde (MDA) in hepatic tissue of intoxicated mice. It had no apparent effect either on the activity of superoxide dismutase (SOD) in mice serum or on the phagocytosis of the monocyte-macrophage system, or on Forssman cutaneous vasculitis and the content of immune complex in serum of rats with Arthus reaction. But it had certain inhibitory effect on the PCA reaction and significant inhibitory effect upon such allergic reaction as Arthus reaction, reversible passive Arthus reaction, the delayed hypersensitivity reaction induced by tuberculin in rats, and adjuvant arthritis.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthus Reaction; Cell Migration Inhibition; Female; Hypersensitivity, Delayed; Inflammation; Male; Mice; Piperidines; Quinolizidines; Rats