Protective effects of paeonol against cognitive impairment in lung diseases.

Pulmonary inflammation may lead to neuroinflammation resulting in neurological dysfunction, and it is associated with a variety of acute and chronic lung diseases. Paeonol is a herbal phenolic compound with anti-inflammatory and anti-oxidative properties. The aim of this study is to understand the beneficial effects of paeonol on cognitive impairment, pulmonary inflammation and its underlying mechanisms. Pulmonary inflammation-associated cognitive deficit was observed in TNFα-stimulated mice, and paeonol mitigated the cognitive impairment by reducing the expressions of interleukin (IL)-1ß, IL-6, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) in hippocampus. Moreover, elevated plasma miR-34c-5p in lung-inflamed mice was also reduced by paeonol. Pulmonary inflammation induced by intratracheal instillation of TNFα in mice resulted in immune cells infiltration in bronchoalveolar lavage fluid, pulmonary edema, and acute fibrosis, and these inflammatory responses were alleviated by paeonol orally. In MH-S alveolar macrophages, tumor necrosis factor (TNF) α- and phorbol myristate acetate (PMA)-induced inflammasome activation was ameliorated by paeonol. In addition, the expressions of antioxidants were elevated by paeonol, and reactive oxygen species production was reduced. In this study, paeonol demonstrates protective effects against cognitive deficits and pulmonary inflammation by exerting anti-inflammatory and anti-oxidative properties, suggesting a powerful benefit as a potential therapeutic agent.

Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers.

Connexins are widely supported as tumor suppressors due to their downregulation in cancers, nevertheless, more recent evidence suggests roles for connexins in facilitating tumor progression in later stages, including metastasis. One of the key factors regulating the expression, modification, stability, and localization of connexins is hormone receptors in hormone-dependent cancers. It is reasonable to consider that hormones/hormone receptors may modulate connexins expression and play critical roles in the cellular control of connexins during breast cancer progression. In estrogen receptor (ER)-positive breast cancers, tamoxifen and fulvestrant are widely used therapeutic agents and are considered to alter ER signaling. In this present study, we investigated the effects of fulvestrant and tamoxifen in Cx43 expression, and we also explored the role of Cx43 in ER-positive breast cancer migration and the relationship between Cx43 and ER. The involvement of estrogen/ER in Cx43 modulation was further verified by administering tyrosine kinase inhibitors and chemotherapeutic agents. We found that inhibition of ER promoted the binding of E3 ligase Nedd4 to Cx43, leading to Cx43 ubiquitination. Furthermore, inhibition of ER by fulvestrant and tamoxifen phosphorylated p38 MAPK, and inhibition of Rac, MKK3/6, and p38 reversed fulvestrant-reduced Cx43 expression. These findings suggest that Cx43 expression which may positively regulate cell migration is ER-dependent in ER-positive breast cancer cells.

The anti-TH17 polarization effect of Indigo naturalis and tryptanthrin by differentially inhibiting cytokine expression.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine Qing-Dai (also known as Indigo naturalis) extracted from indigo-bearing plants including Baphicacanthus cusia (Ness) Bremek was previously reported to exhibit anti-psoriatic effects in topical treatment. TH17 was later established as a key player in the pathogenesis of psoriasis. We investigated the anti-TH17 effect of Indigo naturalis and its active compounds. The aim of this study is to evaluate the toxicity of Indigo naturalis (IN) and its derivatives on five cell types involved in psoriasis, and to study the anti-inflammatory mechanism for the toxicity. MATERIALS AND METHODS: Following the fingerprint and quantity analysis of indirubin, indigo, and tryptanthrin in IN extract, we used MTS kits to measure the anti-proliferative effect of IN and three active compounds on five different cell types identified in psoriatic lesions. Quantitative RT-PCR analysis was used to measure the expression of various genes identified in the activated keratinocytes and TH17 polarized gene expression in RORγt-expressing T cells. RESULTS: We showed that IN differentially inhibited the proliferation of keratinocytes and endothelial cells but not monocytes, fibroblasts nor Jurkat T cells. Among three active compounds identified in IN, tryptanthrin was the most potent compound to reduce their proliferation. In addition to differentially reducing IL6 and IL8 expression, both IN and tryptanthrin also potently decreased the expression of anti-microbial S100A9 peptide, CCL20 chemokine, IL1B and TNFA cytokines, independent of NF-κB-p65-activation. Their attenuating effect was also detected on the expression of signature cytokines or chemokines induced during RORγT-induced TH17 polarization. CONCLUSIONS: We were the first to confirm a direct anti-TH17 effect of both IN herbal extract and tryptanthrin.

Fisetin inhibits cell migration via inducing HO-1 and reducing MMPs expression in breast cancer cell lines.

Metastasis is commonly seen in advanced stage of cancers, and matrix metalloproteinases (MMPs) are commonly up-regulated and have been identified as critical regulators. In this present study, a flavonoid, fisetin, which can be found in diverse foods, is investigated for its ability to inhibit cell motility, and the underlying mechanism is also studied in breast cancer cells (4T1 and JC cells). We have revealed that fisetin increased HO-1 mRNA and protein expressions. Besides, fisetin also elevated Nrf2 expression in nuclear fraction. By silencing Nrf2, fisetin-induced HO-1 expression was abrogated, suggested that HO-1 expression was mediated by up-regulation of the transcription factor Nrf2. In addition, we also found that fisetin decreased MMP-2 and MMP-9 enzyme activity and gene expression in both protein and mRNA levels. Moreover, by administration of HO-1 inhibitors, tin protoporphyrin and zinc protoporphyrin, fisetin-reduced MMP-2 and MMP-9 expressions were reversed. Furthermore, transfection of siRNA against HO-1 and Nrf2 also abolished MMP-2 and MMP-9 reduction exerted by fisetin. These findings suggest that fisetin-mediated MMP-2 and MMP-9 reduction is regulated by HO-1 through Nrf2. Therefore, fisetin may be useful as a potential therapeutic agent for the treatment of metastatic breast cancer.