benzofurans and riligustilide

The treatment of rheumatoid arthritis has changed dramatically over the last two decades since the development of biological disease-modifying anti-rheumatic drugs (bDMARDs). Moreover, Janus kinase (JAK) inhibitors became available in 2013. JAK inhibitors are low-molecular-weight compounds, which exert anti-rheumatic effects by suppressing the action of JAK, an intracellular tyrosine kinase. Of note, biologics bind to extracellular proteins and block their activity. The availability of JAK inhibitors that are as effective as bDMARDs, despite the completely different route of administration and mode of action, has enabled the treatment of rheumatoid arthritis to enter a new stage. JAK inhibitors are useful in a variety of cases, including patients who inadequately responded to treatment with methotrexate and/or bDMARDs. Oral administration is convenient for patients. Nevertheless, the drugs should be carefully prescribed as they are metabolized in the liver and kidneys. Attention should also be paid to adverse events, such as infections including herpes zoster. It is necessary to understand the characteristics of JAK inhibitors and use these agents judiciously.

Topics: Adamantane; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Benzofurans; Cardiovascular Diseases; Herpes Zoster; Humans; Janus Kinases; Molecular Targeted Therapy; Neutropenia; Niacinamide; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides; Venous Thromboembolism

Riligustilide (RG), one of the dimeric phthalides of Angelica sinensis and Ligusticum chuanxiong, was confirmed effective against many diseases. However, its effects on type 2 diabetes mellitus (T2DM) and the underlying molecular mechanisms have not been clearly elucidated yet. The current study was designed to investigate the hypoglycemic potential by which RG affects the pathogenesis of T2DM. Comprehensive insights into the effects and underlying molecular mechanisms of RG on attenuating aberrant metabolism of glucose were determined in high-fat diet-induced T2DM mice and insulin-resistant (IR) HepG2 cells. In high-fat diet-induced C57BL/6J mice, RG administration significantly reduced hyperglycemia, decreased hyperinsulinemia, and ameliorated glucose intolerance. Mechanistically, RG activated PPARγ and insulin signaling pathway to improve insulin sensitivity, and increase glucose uptake as well as glycogenesis. In addition, RG also upregulated AMPK-TORC2-FoxO1 axis to attenuate gluconeogenesis in vivo and in vitro. According to the findings, RG may be a promising candidate for the treatment of T2DM.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Gluconeogenesis; Insulin Resistance; Mice; Mice, Inbred C57BL

Five new phthalide dimers, chaxiongnolides C-G (1-5), the two enantiomers of riligustilide (6a and 6b) and tokinolide B (7) were isolated from the aerial parts of Ligusticum sinense Oliv cv. Chaxiong. The structures of 1-5 were elucidated through extensive spectroscopic analysis, and the relative configurations of compounds 2 and 3 were further confirmed by an X-ray diffraction experiment. The absolute configurations of 1-3 were assigned by comparing calculated and experimental ECD spectra. The ECD exciton chirality method was used to confirm the absolute configurations of compounds 4, 5, 6a and 6b. Compounds 1-3 are the first dimeric phthalides to be reported that are comprising a sedanolide unit. The compounds were evaluated in vitro for their cytotoxic activity against select human cell lines.

Topics: Benzofurans; Cell Line; China; Humans; Ligusticum; Molecular Structure; Phytochemicals; Plant Components, Aerial; Stereoisomerism; X-Ray Diffraction

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Topics: 4-Butyrolactone; Benzofurans; Catalysis; Crystallography, X-Ray; Cycloaddition Reaction; Dimerization; Metals; Molecular Structure; Photochemistry

Nephropathy related with renin can be alleviated with ACE-inhibitors or AT1R blockers, whereas they might be ineffective after long-term administration because of a feedback production of enhanced renin. Therefore, it is urgent to develop a new category of anti-nephropathy medicine directly targeting renin. Riligustilide (C20), originally isolated from the Chinese herb Ligusticumporteri, a rhizome, was confirmed effective against many diseases.. The therapeutic effect of C20 on renal injury and its underlying mechanism were investigated in three different nephrotic models, which were spontaneously hypertension rats (SHR) model, diabetic nephropathy in BTBR ob/ob mice model and 5/6-nephrectomized (5/6NX) rats model.. The intensity of kidney fibrosis was extensively decreased in the C20-treated rats compared to the vehicle animals. C20 significantly alleviated renal injury much more in 5/6 NX rats than in vehicle group. The rats in 5/6 NX without administrated C20 developed albuminuria earlier with more severe symptoms. Additionally, our findings showed that C20 down-regulated the renin expression and relocation of CREB-CBP complex in vivo and in vitro.. C20 plays importantly reno-protective roles most likely through the relocation of CREB-CBP complex.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzofurans; Cell Line; CREB-Binding Protein; Diabetic Nephropathies; Disease Models, Animal; Down-Regulation; Kidney; Male; Medicine, Chinese Traditional; Membrane Proteins; Mice; Mice, Knockout; Mice, Obese; Molecular Docking Simulation; Nephrectomy; Phosphoproteins; Rats; Rats, Inbred SHR; Renin

Seven phthalides, including a new dimeric one named tokinolide C (7), were isolated from Angelicae Sinensis Radix and characterized. The structures of these compounds were elucidated on the basis of comprehensive analysis of spectroscopic data and comparison with literature data. All of the compounds were evaluated for their cytotoxic activities against the A549, HCT-8, and HepG2 cancer cell lines. Riligustilide (4) showed cytotoxicity against three cancer cell lines, with IC50 values of 13.82, 6.79, and 7.92 μM, respectively. Tokinolide A (6) and tokinolide C (6) exerted low cytotoxicity in these cancer cell lines, while the remaining compounds were inactive. Flow cytometry analysis was employed to evaluate the possible mechanism of cytotoxic action of riligustilide (4). We observed that compound 4 was able to arrest the cell cycle in the G1, S phases and induce apoptosis in a time-dependent manner in HCT-8 cell lines. In addition, these compounds were evaluated for neuroprotective effect against SH-SY5Y cells injured by glutamate. The result showed that ligustilide (1), Z-butylidenephthalide (3) and tokinolide A (6) exhibited significant neuroprotective effects.

Topics: Angelica sinensis; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line; Cell Proliferation; Cell Survival; Glutamic Acid; Hep G2 Cells; Humans; Molecular Structure; Neuroprotective Agents; Plant Roots

The presence of dimeric phthalides and other constituents in extracts of the vegetal species Ligusticum porteri was established by NMR spectroscopy. In comparative qualitative (1)H NMR analyses of acetone extracts of rhizomes from fresh and dried L. porteri samples, we found that the dimeric phthalides tokinolide B (3), diligustilide (4) and riligustilide (5) were naturally produced by the plant and not post-harvest products. We also obtained DOSY (1)H NMR data that provided both virtual separation and structural information for the phthalides present in a dry acetone extract of L. porteri. In addition, we developed a protocol for the quantification of dimeric phthalides, which is performed by calculating the relative ratio of the peak area of selected proton signals for some compounds with respect to the known signal of the internal standard, 4-dimethylaminopyridine. The protocol allows the rapid and direct quantification of dimeric phthalides and others constituents in fresh L. porteri rhizomes.

Topics: 4-Aminopyridine; Acetone; Benzofurans; Ligusticum; Magnetic Resonance Spectroscopy; Molecular Structure; Plant Extracts; Protons; Reference Standards; Rhizome; Solvents