STAT3抑制剂（HO-3867）的合成工艺改进

以3,5-二溴-2,2,6,6-四甲基-4-哌啶酮为起始原料,经Favorskii重排和氧化反应的一锅法制得甲基-1-氧基-2,2,5,5-四甲基吡咯烷-3-羧酸甲酯(5a);低温下用四氢铝锂还原5a制得3-羟甲基-1-氧基-2,2,5,5-四甲基吡咯啉(7); 7溴化后与芳胺发生烷基化反应,半连续合成了STAT3抑制剂（HO-3867）,总产率46.3%,其结构经¹H NMR和HR-ESI-MS确证。     

Anti-arthritic and cartilage damage prevention via regulation of Nrf2/HO-1 signaling by glabridin on osteoarthritis

Osteoarthritis is a common degenerative disease linked with inflammatory disorders and oxidative stress. Glabridin is an isoflavonoid and major active constituent of licorice. This study aims to investigate the anti-arthritic effects of glabridin on nuclear factor erythroid 2 – related factor 2 (Nrf2) signaling pathway, inflammatory responses, and cartilage degeneration in in-vitro and in-vivo models. Studies on IL-1β-induced chondrocyte model was performed to evaluate matrix metalloproteinase (MMP), Nrf2 signaling pathway. Glabridin was orally administered in monosodium-iodoacetate (MIA)-induced osteoarthritic (OA) rats for in-vivo evaluation. Pain and swelling of limbs were observed, oxidative stress markers and inflammatory cytokines were measured. Histomorphological changes in the joint cartilage were analyzed. Glabridin significantly reduced the arthritic score and paw swelling along with improved body weight, and organ index of rats. Histopathological score showed significant prevention of joint cartilage degeneration by glabridin. Expressions of TNF-α, IL-6, IL-10, and IL-1β were attenuated by glabridin (p < 0.05) in MIA-induced rats. Protein expressions of iNOS, COX-2, ADAMTS5, MMP-3, and MMP-13 were suppressed (p < 0.05) whereas the Nrf2/HO-1 signaling was activated by glabridin (p < 0.05) in osteoarthritic chondrocytes. Therefore, anti-arthritic and chondroprotective activity of glabridin is suggested by the inhibition of MMP expression and regulation of Nrf2/HO-1 signaling.     

Simultaneous Quantitative Analysis of Ginsenosides Isolated from the Fruit of Panax ginseng C.A. Meyer and Regulation of HO-1 Expression through EGFR Signaling Has Anti-Inflammatory and Osteogenic Induction Effects in HPDL Cells

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.     

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.     

6,7,4′-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways

Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4′-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases.     

A new ocotillol-type ginsenoside from stems and leaves of Panax quinquefolium L. and its anti-oxidative effect on hydrogen peroxide exposed A549 cells

Abstract

A new ocotillol-type ginsenoside, namely 12-one-pseudoginsenoside F₁₁ (12-one-PF₁₁), was isolated from stems and leaves of Panax quinquefolium, whose structure was elucidated 6-O-[α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranosyl]-dammar-12-one-20S,24R-epoxy-3β,6α,25-triol. 12-one-PF₁₁ significantly suppressed hydrogen peroxide induced oxidative stress in human lung carcinoma A549 cells. As compared with model group, 12-one-PF₁₁ improved cell viability of A549 cells in a dose-dependent manner, and significantly decreased the generation of malondialdehyde (MDA) and increased production of superoxide dismutase (SOD) and glutathione (GSH) and protein expression levels of nuclear related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in A549 cells.