AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.
AMP-Activated Protein Kinases ; physiology ; Adiponectin ; pharmacology ; Aminoimidazole Carboxamide ; pharmacology ; Animals ; Enzyme Activation ; Inflammation ; enzymology ; Metformin ; pharmacology ; Pyrones ; pharmacology ; Thiophenes ; pharmacology

OBJECTIVETo study the rubrofusarin glucosides from whole plants of Berchemia polyphylla var. leioclada, and their scavenging activities for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical.

METHODThe chemical constituents were isolated and purified via repeated silica gel and Sephadex LH-20 column chromatography. Their structures were elucidated by spectral analysis and the compounds were tested for their scavenging activities on DPPH radical.

RESULTThree rubrofusarin glucosides compounds were isolated and identified as rubrofusarin-6-O-beta-D-glucopyranoside (1), rubrofusarin-6-O-beta-D-(6'-O-acetyl) glucopyranoside (2), rubrofusarin-6-O-alpha-L-rhamnosyl-(1-6) -O-beta-D-glucopyranside (3). Three isolated compounds showed strong scavenging activities on DPPH radical, the concentration of half elimination ratio( micromol x L(-1)) of VitC and Compounds 1-3 were 18.2, 40.5, 23.3 and 13.6, respectively.

CONCLUSIONCompounds 1-3 were isolated from this plant for the first time and compound 2 was a new compound. They showed significant antioxidant activity, and the scavenging activity of compound 3 was a little stronger than that of VitC.

Biphenyl Compounds ; metabolism ; Free Radical Scavengers ; chemistry ; pharmacology ; Glucosides ; chemistry ; pharmacology ; Nuclear Magnetic Resonance, Biomolecular ; Picrates ; metabolism ; Pyrones ; chemistry ; pharmacology ; Rhamnaceae ; chemistry

AIMTo find derivatives of p-methyl-goniotriol with more potent antitumor activities and lacking undesirable effects.

METHODSEighty derivatives of p-methyl-goniotriol have been synthesized in nine steps from alpha-D-glucoheptonic-delta-lactone (2). Compound 2 reacted with acetone in the catalyzer, H2SO4 and anhydrous MgSO4, and then reacted with 60% aqua HOAc, finally was oxidized by NaIO4 at room temperature into aldehyde 3 in a yield of 71.3%. The aldehyde 3 reacted immediately with P-CH3-PhMgBr giving mixture 4. The mixture 4 was oxidized by NaIO4, reacted with Ph3P = CHCO2Et and then induced by catalyzer. 1,8-Diazabicylclo[5, 4, 0]undec-7-ene in THF providing the compounds 6 and 7. The esterfication of 6 with cinnamyl chloride et al in 4-dimethylaminopyridine, Et3N gave the esters 8a-h. Acid hydrolysis of the acetone protecting group of 8a-h in 75% aqua HOAc gave compounds 9a-h. Their chemical structures were confirmed by IR, 1HNMR, MS and element analysis. The antitumor activities of the compounds were screened by MTT methods.

RESULTSFifteen derivatives of p-methyl-goniotriol (7, 8b-h, 9b-h) are new compounds.

CONCLUSIONPharmacological tests indicate that these compounds showed antitumor activities toward tumor cells (A2780, HCT-8, Bel742, KB) in vitro. The antitumor activities of 8b, 8d, 8g and 9h were more potent than howiinol A.

Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Colonic Neoplasms ; pathology ; Humans ; KB Cells ; Molecular Structure ; Pyrones ; chemical synthesis ; chemistry ; pharmacology ; Tumor Cells, Cultured ; drug effects

PURPOSE: Maltol (3-hydroxy-2-methyl-4-pyrone), formed by the thermal degradation of starch, is found in coffee, caramelized foods, and Korean ginseng root. This study investigated whether maltol could rescue neuroretinal cells from oxidative injury in vitro. METHODS: R28 cells, which are rat embryonic precursor neuroretinal cells, were exposed to hydrogen peroxide (H2O2, 0.0 to 1.5 mM) as an oxidative stress with or without maltol (0.0 to 1.0 mM). Cell viability was monitored with the lactate dehydrogenase assay and apoptosis was examined by the terminal deoxynucleotide transferase-mediated terminal uridine deoxynucleotidyl transferase nick end-labeling (TUNEL) method. To investigate the neuroprotective mechanism of maltol, the expression and phosphorylation of nuclear factor-kappa B (NF-kappaB), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 were evaluated by Western immunoblot analysis. RESULTS: R28 cells exposed to H2O2 were found to have decreased viability in a dose- and time-dependent manner. However, H2O2-induced cytotoxicity was decreased with the addition of maltol. When R28 cells were exposed to 1.0 mM H2O2 for 24 hours, the cytotoxicity was 60.69 ± 5.71%. However, the cytotoxicity was reduced in the presence of 1.0 mM maltol. This H2O2-induced cytotoxicity caused apoptosis of R28 cells, characterized by DNA fragmentation. Apoptosis of oxidatively-stressed R28 cells with 1.0 mM H2O2 was decreased with 1.0 mM maltol, as determined by the TUNEL method. Western blot analysis showed that treatment with maltol reduced phosphorylation of NF-kappaB, ERK, and JNK, but not p38. The neuroprotective effects of maltol seemed to be related to attenuated expression of NF-kappaB, ERK, and JNK. CONCLUSIONS: Maltol not only increased cell viability but also attenuated DNA fragmentation. The results obtained here show that maltol has neuroprotective effects against hypoxia-induced neuroretinal cell damage in R28 cells, and its effects may act through the NF-kappaB and mitogen-activated protein kinase signaling pathways.
Animals ; *Apoptosis ; Blotting, Western ; Cell Survival ; Cells, Cultured ; Disease Models, Animal ; Flavoring Agents/pharmacology ; In Situ Nick-End Labeling ; Oxidative Stress/*drug effects ; Pyrones/*pharmacology ; Rats ; Retinal Ganglion Cells/drug effects/metabolism/*pathology

AIMTo seek for new components as BACE inhibitors from Aloe arborescens.

METHODSThe chemical constituents were isolated by chromatographic methods and their structures were elucidated on the basis of spectral analysis.

RESULTSEight compounds were isolated and their structures identified as 6'-O-isobutyryl aloenin A (1), aloenin A (2), aloe-emodin (3), (E)-2-acetonyl-8-(2'-O-feruloxyl)-beta-D-glucopyranosyl-7-methoxy-5-methyl-chromone (4), 7-O-methylaloeresin A (5), babarloin A (6), elgonica-dimer A (7), and elgonica-dimer B (8), separately.

CONCLUSIONCompound 1 is a new compound, and compound 4 was isolated from A. arborescens for the first time. Pharmacological tests indicated that 2, 4, 5 and 6 have moderate inhibitory active on BACE.

Aloe ; chemistry ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; metabolism ; Anthraquinones ; chemistry ; isolation & purification ; pharmacology ; Aspartic Acid Endopeptidases ; antagonists & inhibitors ; metabolism ; Chromones ; chemistry ; isolation & purification ; pharmacology ; Enzyme Inhibitors ; chemistry ; isolation & purification ; pharmacology ; Glucosides ; chemistry ; isolation & purification ; pharmacology ; Humans ; Molecular Conformation ; Molecular Structure ; Plant Components, Aerial ; chemistry ; Plant Extracts ; chemistry ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Pyrones ; chemistry ; isolation & purification ; pharmacology

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. The gene mutated in this disease, ATM (A-T, mutated), encodes a 370-kDa Ser/Thr protein kinase. ATM not only mediates cellular response to DNA damage but also acts as an activator of Akt in response to insulin. However, despite intensive studies, the mechanism underlying the neuronal degeneration symptoms of human A-T is still poorly understood. We found that the topoisomerase inhibitors etoposide and camptothecin readily induced apoptosis in undifferentiated proliferating SH-SY5Y cells but could not induce apoptosis in neuronally differentiated SH-SY5Y cells. In addition, etoposide induced p53 phosphorylation and H2AX foci formation in proliferating SH-SY5Y cells but failed to do so in differentiated SH-SY5Y cells. Moreover, while inhibition of ATM in undifferentiated SH-SY5Y cells partially protected them from etoposide-induced apoptosis, the same treatment had no effect on cell viability in differentiated SH-SY5Y cells. These results suggest that DNA damage or defective response to DNA damage is not the cause of neuronal cell death in human A-T. In contrast, we discovered that Akt phosphorylation was inhibited when ATM activity was suppressed in differentiated SH-SY5Y cells. Furthermore, inhibition of ATM induced apoptosis following serum starvation in neuronally differentiated SH-SY5Y cells but could not trigger apoptosis under the same conditions in undifferentiated proliferating SH-SY5Y cells. These results demonstrate that ATM mediates the Akt signaling and promotes cell survival in neuron-like human SH-SY5Y cells, suggesting that impaired activation of Akt is the reason for neuronal degeneration in human A-T.
Antineoplastic Agents, Phytogenic ; pharmacology ; Apoptosis ; Ataxia Telangiectasia ; pathology ; Ataxia Telangiectasia Mutated Proteins ; Camptothecin ; pharmacology ; Cell Cycle Proteins ; antagonists & inhibitors ; metabolism ; Cell Differentiation ; Cell Line, Tumor ; DNA Damage ; DNA-Binding Proteins ; antagonists & inhibitors ; metabolism ; Etoposide ; pharmacology ; Histones ; metabolism ; Humans ; Morpholines ; pharmacology ; Neuroblastoma ; pathology ; Neurons ; cytology ; Phosphorylation ; Protein-Serine-Threonine Kinases ; antagonists & inhibitors ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyrones ; pharmacology ; Signal Transduction ; Topoisomerase Inhibitors ; pharmacology ; Tumor Suppressor Protein p53 ; metabolism ; Tumor Suppressor Proteins ; antagonists & inhibitors ; metabolism