Nuclear factor-kB (NF-kB) is a dimeric transcription factor that activates the expression of many genes involved in the inflammatory process, e.g., the cytokines IL-1b, IL-2, and TNF-a, adhesion molecules, and enzymes such as iNOS, cyclooxygenase-II, and 5-lipoxygenase.1) NF-kB is inactive without stimulation, and it is activated by extracellular signals such as TNF-a, IL-1, lipopolysaccharide (LPS), UV light, and phorbol esters. In unstimulated cells, NF-kB is retained in the cytoplasm via interaction with its inhibitor IkB. In response to various proinflammatory stimuli, IkB is phosphorylated by IkB kinase complex. This leads to the ubiquitination and subsequent proteasome-mediated degradation of IkB, allowing NF-kB to enter the nucleus. NF-kB is highly activated at the site of inflammation of diverse diseases such as rheumatoid arthritis, atherosclerosis, asthma, inflammatory bowel disease, and Helicobacter pylori-associated gastritis 1) and associated with cancer, cachexia, diabetes, euthyroid sick syndrome, and AIDS.2) With its apparent involvement in a variety of human diseases, NF-kB has been shown to be the target of several anti-inflammatory and anticancer drugs. 2)In our search for inhibitors of NF-kB activity from natural products, the MeOH extract of the stem bark of Alnus hirsuta showed significant inhibitory activity of NF-kB activation (IC 50 value, 16.5 mg/ml). The species A. hirsuta belongs to the Betulaceae, and geographically distributes in Korea, Japan, Northeast China, and Russia. It is a broad-leaved deciduous tree that grows in damp places. The bark of this species has been used in Chinese and Korean traditional medicine as a remedy for fever, hemorrhage, diarrhea, and alcoholism.3) Previous studies on the chemical constituents of A. hirsuta have led to the isolation of various natural products such as tannins, 4,5) flavonoids, 6,7) diarylheptanoids, [8][9][10] and triterpenoids.11) It has also been reported to exhibit a variety of bioactivities such as antioxidant activity, 12,13) antiinflammation, 14) cytotoxicity, and antitumor effects. [15][16][17][18] Here we describe the isolation and effects of six diarylheptanoids (1-6) from the stem bark of A. hirsuta on LPS-induced NFkB activation, on nitric oxide (NO) production, and on tumor necrosis factor-a (TNF-a) production in LPS-stimulated RAW264.7 cells. MATERIALS AND METHODS Plant MaterialThe stem bark of Alnus hirsuta TURCZ. was collected at Yangu, Kangwon, Korea in Aug. 2002 and the plant was identified by one of the authors, Prof. KiHwan Bae. The voucher specimen (CNU-0304) has been deposited at the herbarium of Chungnam National University, Daejeon, Korea.General Experimental Procedures Optical rotations were measured by JASCO DIP-370 digital polarimeter. IR spectra were taken on a JASCO Report-100 spectrometer (KBr pellet). FAB-MS were obtained using a JEOL JMS-DX 300 spectrometer.1 H-NMR (300 MHz), 13C-NMR (75 MHz), and DEPT data were obtained on a Varian Unity NMR spectrometer. High-performance liquid chromatography (HPLC) was ca...
Cytotoxic bioassay-guided fractionation of methanol extract of Angelicae Sinensis Radix led to the isolation of a new dimeric Z-ligustilide, named neodiligustilide (1), together with three known compounds, Z-ligustilide (2), 11(S),16(R)-dihydroxy-octadeca-9Z, 17-dien-12,14-diyn-1-yl acetate (3), and 3(R),8(S)-falcarindiol (4). Among them, 2 showed the strongest cytotoxicity against L1210 and K562 cell lines with IC50 values of 2.27 +/- 0.10 and 4.78 +/- 0.18 microM, respectively, while 1 showed moderate cytotoxicity with IC50 values of 5.45 +/- 0.19 and 9.87 +/- 0.14 microM. Two polyacetylenes, 3 and 4, showed cytotoxicity only against L1210 cell line with IC50 values of 2.60 +/- 0.90 and 2.87 +/- 0.49 microM, respectively.
IntroductionDespite the many benefits immunotherapy has brought to patients with different cancers, its clinical applications and improvements are still hindered by drug resistance. Fostering a reliable approach to identifying sufferers who are sensitive to certain immunotherapeutic agents is of great clinical relevance.MethodsWe propose an ELISE (Ensemble Learning for Immunotherapeutic Response Evaluation) pipeline to generate a robust and highly accurate approach to predicting individual responses to immunotherapies. ELISE employed iterative univariable logistic regression to select genetic features of patients, using Monte Carlo Tree Search (MCTS) to tune hyperparameters. In each trial, ELISE selected multiple models for integration based on add or concatenate stacking strategies, including deep neural network, automatic feature interaction learning via self-attentive neural networks, deep factorization machine, compressed interaction network, and linear neural network, then adopted the best trial to generate a final approach. SHapley Additive exPlanations (SHAP) algorithm was applied to interpret ELISE, which was then validated in an independent test set.ResultRegarding prediction of responses to atezolizumab within esophageal adenocarcinoma (EAC) patients, ELISE demonstrated a superior accuracy (Area Under Curve [AUC] = 100.00%). AC005786.3 (Mean [|SHAP value|] = 0.0097) was distinguished as the most valuable contributor to ELISE output, followed by SNORD3D (0.0092), RN7SKP72 (0.0081), EREG (0.0069), IGHV4-80 (0.0063), and MIR4526 (0.0063). Mechanistically, immunoglobulin complex, immunoglobulin production, adaptive immune response, antigen binding and others, were downregulated in ELISE-neg EAC subtypes and resulted in unfavorable responses. More encouragingly, ELISE could be extended to accurately estimate the responsiveness of various immunotherapeutic agents against other cancers, including PD1/PD-L1 suppressor against metastatic urothelial cancer (AUC = 88.86%), and MAGE−A3 immunotherapy against metastatic melanoma (AUC = 100.00%).DiscussionThis study presented deep insights into integrating ensemble deep learning with self-attention as a mechanism for predicting immunotherapy responses to human cancers, highlighting ELISE as a potential tool to generate reliable approaches to individualized treatment.
Glucose uptake assay-guided fractionations on the methanol extract of Sophorae Flos led to the isolation of the flavonoids rutin (1), narcissin (2), quercetin (3), tamarixetin (4), and kaempferol (5) and the isoflavonoids cajanin (6), genistein (7), orobol (8), and pratensein (9). Among them, 1, 4, 5, 6, 8, and 9 significantly improved basal glucose uptake in HepG2 cells. Their improving effects were concentration dependent. Compounds 4, 5, 6, and 9 exhibited effects stronger than that of rosiglitazone, which has been used as an antidiabetic drug. However, 2, 3, and 7 did not show any improving effects. Stimulating glucose uptake into peripheral cells may be responsible for reducing the level of blood glucose in the circulation. Therefore, these findings demonstrate a potential to develop these flavonoids and isoflavonoids as hypoglycemic drugs.
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