Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.

Periodontitis is a set of chronic inflammatory diseases caused by the accumulation of Gram-negative bacteria on teeth, resulting in gingivitis, pocket formation, alveolar bone loss, tissue destruction, and tooth loss. In this study, the contents of ginsenosides isolated from Panax ginseng fruit extract were quantitatively analyzed, and the anti-inflammatory effects were evaluated in human periodontal ligament cells. The major ginsenosides, Re, Ra8, and Rf, present in ginseng fruit were simultaneously analyzed by a validated method using high-performance liquid chromatography with a diode-array detector; Re, Ra8, and Rf content per 1 g of P. ginseng fruit extract was 1.01 ± 0.03, 0.33 ± 0.01, and 0.55 ± 0.04 mg, respectively. Ginsenosides-Re, -Ra8, and -Rf inhibited the production of pro-inflammatory factors and the expression of important cytokines in periodontitis by inducing the expression of heme oxygenase 1 (HO-1), promoting osteoblast differentiation of periodontal ligament cells, suppressing alveolar bone loss, and promoting the expression of osteoblast-specific genes, such as alp, opn, and runx2. An inhibitory effect of these ginsenosides on periodontitis and alveolar bone loss was observed via the regulation of HO-1 and subsequent epidermal growth factor receptor (EGFR) signaling. Silencing EGFR with EGFR siRNA confirmed that the effect of ginsenosides on HO-1 is mediated by EGFR. In conclusion, this study evaluated the contents of ginsenosides-Re, -Ra8, and -Rf isolated from P. ginseng fruit extract. Therefore, these results provide important basic data for future P. ginseng fruit component studies and suggest that ginsenosides Re, Ra8, and Rf have potential as future treatment options for periodontitis.

While liquiritigenin, isolated from Spatholobus suberectus Dunn, is known to possess anti-inflammatory activities, it still remains to be known whether liquiritigenin has a suppressive effect on T cell activation and T cell-mediated disease. Here, we used Jurkat T cells to explore an underlying mechanism of pre-treatment with liquiritigenin in activated T cell in vitro and used atopic dermatitis (AD) in vivo to confirm it. We found liquiritigenin blocks IL-2 and CD69 expression from activated T cells by PMA/A23187 or anti-CD3/CD28 antibodies. The expressions of surface molecules, including CD40L and CD25, were also reduced in activated T cells pre-treated with liquiritigenin. Western blot analysis indicated repressive effects by liquiritigenin are involved in NFκB and MAPK pathways. To assess the effects of liquiritigenin in vivo, an AD model was applied as T cell-mediated disease. Oral administration of liquiritigenin attenuates AD manifestations, including ear thickness, IgE level, and thicknesses of dermis and epidermis. Systemic protections by liquiritigenin were observed to be declined in size and weight of draining lymph nodes (dLNs) and expressions of effector cytokines from CD4⁺ T cells in dLNs. These results suggest liquiritigenin has an anti-atopic effect via control of T cell activation and exhibits therapeutic potential for T cell-mediated disorders.

The appropriate regulation of T cell activity under inflammatory conditions is crucial for maintaining immune homeostasis. Salinosporamide A discovered as a self-resistance product from the marine bacterium Salinospora tropica, has been used as a potent proteasome inhibitor (PI). Although PIs have been developed as novel therapeutics for autoimmune diseases, due to their immunosuppressive effect, whether salinosporamide A inhibits T cell activation remains unknown. The current study finds that salinosporamide A is not cytotoxic, but controls T cell proliferation. Results from our cell cycle arrest analysis revealed that salinosporamide A leads to cell cycle arrest and regulates the expression of cyclin-dependent kinases. Under activated conditions, salinosporamide A abrogated T cell activation by T cell receptor-mediated stimulation, in which the production of cytokines was inhibited by pretreatment with salinosporamide A. Furthermore, we demonstrated that the regulation of T cell activation by salinosporamide A is mediated by suppressing the MAPK pathway. Therefore, our results suggest that salinosporamide A effectively suppresses T cell activation through regulating T cell proliferation and the cell cycle and provides great insight into the development of novel therapeutics for autoimmune diseases or graft-versus-host disease.

Methamphetamine (METH) is an addictive psychostimulant showing neurotoxicity through neuronal apoptosis and the neuro-inflammatory pathway. Lupenone, a lupane triterpenoid, is an isolated compound exhibiting anti-oxidative, anti-inflammation, and anti-diabetic activities. However, whether lupenone plays a protective role against apoptosis induced by METH in SH-SY5y neuroblastoma cells remains unknown. In the present study, we elucidated that lupenone had no toxicity to SH-SY5y cells at different concentrations. On the other hand, we found that the treatment of SH-SY5y cells with an optimal concentration of lupenone could lead to protection against cell death induced by METH. AnnexinV/PI apoptosis analysis revealed a dramatically reduced level of the apoptotic cell population in lupenon and METH treated SH-SY5y cells. Moreover, diminished expression of anti-apoptotic proteins, including Bcl-2, Caspase3, Caspase7, and Caspase8 in METH-exposed SH-SY5y cells, was significantly recovered by treatment with lupenone. This protection in the expression of anti-apoptotic proteins was due to an increased phosphorylation level of PI3K/Akt in METH-treated SH-SY5y cells pre-incubated with lupenone. These findings suggest that lupenone can protect SH-SY5y cells against METH-induced neuronal apoptosis through the PI3K/Akt pathway.

Osteoarthritis (OA) is a common joint degenerative disease induced by oxidative stress in chondrocytes. Although induced-heme oxygenase-1 (HO-1) has been found to protect cells against oxygen radical damage, little information is available regarding the use of bioactive compounds from natural sources for regulating the HO-1 pathway to treat OA. In this study, we explored the inhibitory effects of cudratricusxanthone O (CTO) isolated from the Maclura tricuspidata Bureau (Moraceae) on H₂O₂-induced damage of SW1353 chondrocytes via regulation of the HO-1 pathway. CTO promoted HO-1 expression by enhancing the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus without inducing toxicity. Pretreatment with CTO-regulated reactive oxygen species (ROS) production by inducing expression of antioxidant enzymes in H₂O₂-treated cells and maintained the functions of H₂O₂-damaged chondrocytes. Furthermore, CTO prevented H₂O₂-induced apoptosis by regulating the expression of anti-apoptotic proteins. Treatment with the HO-1 inhibitor tin-protoporphyrin IX revealed that these protective effects were exerted due to an increase in HO-1 expression induced by CTO. In conclusion, CTO protects chondrocytes from H₂O₂-induced damages—including ROS accumulation, dysfunction, and apoptosis through activation of the Nrf2/HO-1 signaling pathway in chondrocytes and, therefore, is a potential therapeutic agent for OA treatment.