We synthesized a mitochondria-targeted honokiol (Mito-HNK) that facilitates its mitochondrial accumulation; this dramatically increases its potency and efficacy against highly metastatic lung cancer lines in vitro, and in orthotopic lung tumor xenografts and brain metastases in vivo. Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation, inhibiting mitochondrial complex ?, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3. Within lung cancer brain metastases in mice, Mito-HNK induced the mediators of cell death and decreased the pathways that support invasion and proliferation. In contrast, in the non-malignant stroma, Mito-HNK suppressed pathways that support metastatic lesions, including those involved in inflammation and angiogenesis. Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers. Its pronounced anti-invasive and anti-metastatic effects in the brain are particularly intriguing given the paucity of treatment options for such patients either alone or in combination with standard chemotherapeutics.

• Publikační typ
• časopisecké články MeSH

Kůra magnolií je silně aromatický rostlinný materiál, získávaný především z Magnolia officinalis L. a M. obovata L. (čeleď Magnoliaceae). V tradiční východní medicíně je používána jako droga k mnoha účelům, zejména jako mírně účinkující uklidňující prostředek. Hlavními obsahovými látkami drogy jsou fenoly odvozené od bifenylu, magnolol a honokiol, a některé další biologicky aktivní látky. Vykazují řadu farmakologických efektů, z nichž nejvýznamnější jsou antioxidační a sedativní účinky a pozitivní vliv na kognitivní funkce.

Magnolia bark is a highly aromatic herbal material obtained from Magnolia officinalis, of the Family Magnoliaceae. In traditional oriental medicine this herbal drug is used for many purposes, especially as a mild tranquilizer. Principal substantial compounds of this drug are biphenol compounds, magnolol and honokiol, and some other biologically active compounds. They exert a lot of pharmacological actions, among which the most important are antioxidant and sedative effects and assertive influence on cognitive functions.

• MeSH
• anxiolytika farmakologie   chemie   terapeutické užití   MeSH
• fenoly farmakologie   chemie   MeSH
• krysa rodu rattus MeSH
• kůra rostlin MeSH
• léčivé rostliny MeSH
• lidé MeSH
• Magnoliaceae MeSH
• psychotropní léky farmakologie   chemie   MeSH
• rostlinné přípravky farmakologie   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH

This review summarizes our work in the field of syn-thesis of natural products and their derivatives. Applica-tion of modern synthetic method is discussed in the con-text of the syntheses of both enantiomers of hydromor-phone, (–)-tetrodotoxin (a marine toxin), and selaginpul-vilins C and D (natural fluorene derivatives). Further, syn-thesis of notoincisol A, selagibenzophenones A and B is described to clarify the structural aspects of the com-pounds. Last but not least, synthesis and pharmaceutical profilation of derivatives of magnolol and honokiol is dis-cussed as well.Fulltext of this article is available on the website of this Journal.

• MeSH
• alkyny chemická syntéza   chemie   MeSH
• biologické přípravky MeSH
• hydromorfon chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• lignany chemická syntéza   chemie   MeSH
• polyacetyleny chemická syntéza   chemie   MeSH
• polycyklické sloučeniny chemická syntéza   chemie   MeSH
• Selaginellaceae chemie   MeSH
• techniky syntetické chemie * metody   MeSH
• tetrodotoxin chemická syntéza   chemie   farmakologie   MeSH
• vyvíjení léků MeSH
• Check Tag
• lidé MeSH

Pulmonary hypertension (PH) is a heterogeneous and life-threatening cardiopulmonary disorder in which mitochondrial dysfunction is believed to drive pathogenesis, although the underlying mechanisms remain unclear. To determine if abnormal SIRT3 (sirtuin 3) activity is related to mitochondrial dysfunction in adventitial fibroblasts from patients with idiopathic pulmonary arterial hypertension (IPAH) and hypoxic PH calves (PH-Fibs) and whether SIRT3 could be a potential therapeutic target to improve mitochondrial function, SIRT3 concentrations in control fibroblasts, PH-Fibs, and lung tissues were determined using quantitative real-time PCR and western blot. SIRT3 deacetylase activity in cells and lung tissues was determined using western blot, immunohistochemistry staining, and immunoprecipitation. Glycolysis and mitochondrial function in fibroblasts were measured using respiratory analysis and fluorescence-lifetime imaging microscopy. The effects of restoring SIRT3 activity (by overexpression of SIRT3 with plasmid, activation SIRT3 with honokiol, and supplementation with the SIRT3 cofactor nicotinamide adenine dinucleotide [NAD+]) on mitochondrial protein acetylation, mitochondrial function, cell proliferation, and gene expression in PH-Fibs were also investigated. We found that SIRT3 concentrations were decreased in PH-Fibs and PH lung tissues, and its cofactor, NAD+, was also decreased in PH-Fibs. Increased acetylation in overall mitochondrial proteins and SIRT3-specific targets (MPC1 [mitochondrial pyruvate carrier 1] and MnSOD2 [mitochondrial superoxide dismutase]), as well as decreased MnSOD2 activity, was identified in PH-Fibs and PH lung tissues. Normalization of SIRT3 activity, by increasing its expression with plasmid or with honokiol and supplementation with its cofactor NAD+, reduced mitochondrial protein acetylation, improved mitochondrial function, inhibited proliferation, and induced apoptosis in PH-Fibs. Thus, our study demonstrated that restoration of SIRT3 activity in PH-Fibs can reduce mitochondrial protein acetylation and restore mitochondrial function and PH-Fib phenotype in PH.

• MeSH
• fibroblasty metabolismus   MeSH
• lidé MeSH
• mitochondriální proteiny metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• NAD metabolismus   MeSH
• plicní hypertenze * patologie   MeSH
• sirtuin 3 * genetika   metabolismus   MeSH
• skot MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH