Solving a traditional Chinese medicine mystery

Researchers at the Johns Hopkins School of Medicine have discovered that a natural product isolated from a traditional Chinese medicinal plant commonly known as thunder god vine, or lei gong teng, and used for hundreds of years to treat many conditions including rheumatoid arthritis works by blocking gene control machinery in the cell. The report, published as a cover story of the March issue of Nature Chemical Biology, suggests that the natural product could be a starting point for developing new anticancer drugs.

"Extracts of this medicinal plant have been used to treat a whole host of conditions and have been highly lauded for anti-inflammatory, immunosuppressive, contraceptive and antitumor activities," says Jun O. Liu, Ph.D., a professor of pharmacology and molecular sciences at Johns Hopkins. "We've known about the active compound, triptolide, and that it stops cell growth, since 1972, but only now have we figured out what it does."

Triptolide, the active ingredient purified from the plant Tripterygium wilfordii Hook F, has been shown in animal models to be effective against cancer, arthritis and skin graft rejection. In fact, says Liu, triptolide has been shown to block the growth of all 60 U.S. National Cancer Institute cell lines at very low doses, and even causes some of those cell lines to die. Other experiments have suggested that triptolide interferes with proteins known to activate genes, which gives Liu and colleagues an entry point into their research.

The team systematically tested triptolide's effect on different proteins involved with gene control by looking at how much new DNA, RNA and protein is made in cells. They treated HeLa cells with triptolide for one hour, compared treated to untreated cells and found that triptolide took much longer to have an effect on the levels of newly made proteins and DNA, yet almost immediately blocked manufacture of new RNA. The researchers then looked more closely at the three groups of enzymes that make RNA and found that low doses of triptolide blocked only one, RNAPII.

But the RNAPII enzyme complex actually requires the assistance of several smaller clusters of proteins, according to Liu, which required more investigative narrowing down. Using a small gene fragment in a test tube, the researchers mixed in RNAPII components and in some tubes included triptolide and some not to see which combinations resulted in manufacture of new RNA. Every combination of proteins that included a cluster called TFIIH stopped working in the presence of triptolide.

But again, TFIIH is made of 10 individual proteins, many of which, according to Liu, have distinct and testable activities. Using information already known about these proteins and testing the rest to see if triptolide would alter their behaviors, the research team finally found that triptolide directly binds to and blocks the enzymatic activity of one of the 10, the XPB protein.

"We were fairly certain it was XPB because other researchers had found triptolide to bind to an unknown protein of the same size, but they weren't able to identify it," says Liu. "

To convince themselves that the interaction between triplotide and XPB is what stops cells from growing, the researchers made 12 chemicals related to triplotide with a wide range of activity and treated HeLa cells with each of the 12 chemicals at several different doses. By both counting cells and testing XPB activity levels, the team found that the two correlate; chemicals that were better at decreasing XPB activity were also better at stopping cell growth and vice versa.

"Triptolide's general ability to stop RNAPII activity explains its anti-inflammatory and anticancer effects," says Liu. "And its behavior has important additional implications for circumventing the resistance that some cancer cells develop to certain anticancer drugs. We're eager to study it further to see what it can do for future cancer therapy."

Provided by Johns Hopkins Medical Institutions

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Discovery of blood proteins that are red flags for ectopic pregnancy

 A long, urgent search for proteins in the blood of pregnant women that could be used in early diagnosis of ectopic pregnancy (EP) has resulted in discovery of biomarkers that seem to be specific enough to begin testing in clinical trials, scientists are reporting in a new study in ACS's Journal of Proteome Research.

David Speicher and colleagues explain that ectopic pregnancy happens when an embryo does not attach normally inside the mother's uterus, but instead attaches and begins growing elsewhere. Most occur inside one of the Fallopian tubes, which link the ovaries to the uterus. Left undiagnosed, EP can burst the Fallopian tube and result in bleeding that is the second most common cause of maternal death early in the first trimester of pregnancy. EP is difficult for doctors to diagnose, and scientists long have searched for substances present in the blood of women with EP that could be the basis for a test.

The scientists describe discovery of such proteins in blood analyzed from women with ectopic pregnancies and compared it to blood of women with normal pregnancies. They identified almost 70 proteins occurring in unusual levels in the blood in EPs. One of those proteins is called Adam12 and it might be a particularly good early warning sign for EP, since it appears at levels that are 20 times lower than in normal pregnancies. "The next step is clearly to test the candidate biomarkers on a larger, independent patient group, both individually and in multi-biomarker panels," the report states.

More information: "Systematic Discovery of Ectopic Pregnancy Serum Biomarkers Using 3-D Protein Profiling Coupled with Label-free Quantitation", Journal of Proteome Research.

Microbially produced ferrous iron may decrease technetium concentrations in groundwater

The long-lasting radionuclide technetium is transported through the subsurface near former nuclear production and processing sites, moving toward rivers and lakes. But its journey can come to an abrupt end if it hits an area containing high levels of reduced iron generated by microbes.

Scientists from Pacific Northwest National Laboratory recently found that microbially generated iron creates significant roadblocks for the pollutant. They determined that in the presence of commonly occurring oxidized iron minerals, indirect technetium reduction by microbially generated ferrous iron, or Fe(II), may be favored over direct technetium reduction by bacteria, making the technetium as much as 10 times less soluble.

Technetium-99 (99Tc), a radioactive by-product of nuclear production and processing, has a half-life of 200,000 years. Its common oxidized form, Tc(VII)O4-, or pertechnetate, is highly mobile in subsurface sediments and groundwater. This makes it of concern at Department of Energy plutonium production sites such as the Hanford Site in Washington State, and others in Paducah, KY, and Portsmouth, OH.

Fortunately, pertechnetate can be chemically reduced to less mobile forms by subsurface minerals containing reduced or ferrous (Fe2+) iron. The ferrous iron content of the subsurface can, in turn, be increased by metal-reducing bacteria, such as Shewanella, Geobacter, and Anaeromyxobacter.

The tenfold difference in technetium solubility is important, because the Environmental Protection Agency limit for 99Tc in drinking water is extremely low—near the solubility value for the chemically reduced form of Tc, TcO2 (technetium dioxide). Furthermore, the PNNL researchers found that direct biological reduction of technetium by metal-reducing bacteria generated small-particle technetium colloids that could be highly mobile. Previous research revealed that technetium oxide associated with minerals can be resistant to reoxidation and mobility.

Pertechnetate can be reduced to technetium oxide or to various Tc(IV) chemical phases by microbial enzymes that can generate low redox potential, such as hydrogenase or c-type cytochromes. Various forms of reduced inorganic ions, such as ferrous iron or sulfide are also produced and these, have the potential to reduce pertechnetate. The effectiveness of these reductants is extremely dependent on their chemical speciation and mineral form.

Using several dissimilatory metal-reducing bacteria, the PNNL team examined the bioreduction of pertechnetate in the presence and absence of the poorly crystalline iron oxide. They examined the resulting bioreduced materials by transmission electron microscopy, X-ray absorption spectroscopy, microcapillary X-ray diffraction, and traditional wet-chemical analytical methods. Technetium solubility was determined by sequential ultrafiltration, solvent extraction, and liquid scintillation counting.

The researchers are now examining the enzymatic reduction of technetium by hydrogenase and cytochromes to gain insight into the properties of biogenic technetium oxide and the electron transfer mechanisms responsible for the reduction. Simultaneously, they are examining the biogeochemical transformation reactions in representative Hanford Site sediments and the microbial and geochemical catalysts responsible for technetium reduction.

More information: Plymale AE, JK Fredrickson, JM Zachara, AC Dohnalkova, SM Heald, DA Moore, DW Kennedy, MJ Marshall, C Wang, CT Resch, and P Nachimuthu. 2011. "Competitive Reduction of Pertechnetate (99TcO4-) by Dissimilatory Metal Reducing Bacteria and Biogenic Fe(II)." Environmental Science & Technology 45(3):951-957. DOI:10.1021/es1027647

 

Fingerprints of a gold cluster revealed

 

Nanometre-scale gold particles are currently intensively investigated for possible applications in catalysis, sensing, photonics, biolabelling, drug carriers and molecular electronics. The particles are prepared in a solution from gold salts and their reactive gold cores can be stabilised with various organic ligands. Particularly stable particles can be synthesised by using organothiolate ligands that have a strong chemical interaction to gold. The chemical process of preparing such particles has been known since the mid-1990s and many different stable sizes and compositions are known.

However, the first definite information of their atomic structure became available only in 2007 when the group of Roger Kornberg (Chemistry Nobel Laureate 2006) at Stanford University succeeded in making single crystals for X-ray diffractometry containing only one type of a particle having 102 gold atoms and 44 thiolate ligands, the so called Au102(p-MBA)44 particle. The structure was reported in Science in late 2007 [1]. The theoretical analysis of this and other thiolate-protected gold clusters, led by Professor Hannu Häkkinen at the University of Jyväskylä in Finland, resulted in a theoretical framework that can be used to understand the stability and electronic structure of these particles. This work was reported in the Proceedings of the National Academy of Sciences in 2008 [2].

Now, researchers in the Department of Chemistry and the Nanoscience Center (NSC) at the University of Jyväskylä, in collaboration with the Kornberg group, report the first full spectroscopic characterisation of the absorption of electromagnetic radiation by the Au102(p-MBA)44 particle in solution and solid phases. The study was published in the Journal of the American Chemical Society on 24 February 2011 [3]. The spectroscopic study was performed in a large range of electromagnetic spectrum from mid-infrared ("heat absorption") to ultraviolet light.

"The study was technically demanding and could only be made now when the Stanford group has succeeded in refining the synthesis to produce pure Au102(p-MBA)44 product in large quantities," explains Adjunct Professor Mika Pettersson, who led the experimental work at the NSC. "We document clear "fingerprint" features in the absorbance spectrum that can be used in the future to benchmark chemical modifications of this particle for various applications. The work also establishes the molecular nature of the clusters by the observation of a band gap of 0.45 eV, in excellent agreement with theory. We were able to analyse these features from large-scale computations using the known structure of Au102(p-MBA)44 and thus fully understand the absorption characteristics of this particle," says Professor Häkkinen.

More information: 1. P.D. Jadzinsky, G. Calero, C.J. Ackerson, D.A. Bushnell and R.D. Kornberg, "Structure of a thiol monolayer-protected gold nanoparticle at 1.1. Angstrom resolution", Science 318, 430 (2007) (www.sciencemag.org/content/318/5849/430.abstract).

2. M. Walter, J. Akola, O. Lopez-Acevedo, P. D. Jadzinsky, G. Calero, C. J. Ackerson, R. L. Whetten, H. Grönbeck, H. Häkkinen, "A unified view of ligand-protected gold clusters as superatom complexes", Proc. Natl. Acad. Sci. (USA) 105, 9157 (2008) (www.pnas.org/content/105/27/9157). See also http://gtresearchn … lusters.htm.

3. E. Hulkko, O. Lopez-Acevedo, J. Koivisto, Y. Levi-Kalisman, R.D. Kornberg, M. Pettersson and H. Häkkinen, "Electronic and vibrational signatures of the Au102(p-MBA)44 cluster", J. Am. Chem. Soc., online Communication February 24, 2011 : (http://pubs.acs.or … 21/ja111077e)

Provided by Academy of Finland

Food scientist develops 'rechargeable' anti-microbial surfaces to improve food-handling safety

 Using nano-scale materials, a University of Massachusetts Amherst food scientist is developing a way to improve food safety by adding a thin anti-microbial layer to food-handling surfaces. Only tens of nanometers thick, it chemically "re-charges" its germ-killing powers every time it’s rinsed with common household bleach.

Food scientist Julie Goddard recently received a four-year, $488,000 grant from the United States Department of Agriculture’s Agriculture and Food Research Initiative to lead the development of the new method for modifying polymer and stainless steel processing surfaces by adding a nano-scale layer of antimicrobial compound to gaskets, conveyor belts and work tables, for example.

As she explains, "This layer replenishes its anti-microbial qualities with each repeated bleach rinse. So at the end of the day in a meat-packing plant, for example, when employees clean their equipment, the regular bleach rinse will re-charge the surface’s anti-microbial activity. They will not need to add any more steps." The chemical action comes from a halamine structure that holds chlorine in an applied layer only nanometers thick. The treatment does not affect the strength of tables or trays.

Food production is increasingly automated and as the number of surfaces contacted by food increases, there is greater potential for contamination. Goddard and colleagues’ new method will cost industry less than incorporating anti-microbials into an entire conveyor belt construction, for example. The technique is effective at the square-inch scale in the laboratory now, the food scientist adds, and a major goal will be to show that it can be effective at larger scales in commercial food processing.

Goddard, who did the preliminary work to show that this nanotech method is effective against organisms relevant to food safety and others relevant to food spoilage, such as E. coli and Listeria, says the technology is already being applied in hospital textiles whose anti-microbial properties are replenished each time they’re laundered in bleach.

"It’s not meant to replace thorough cleaning, which should always be in place, but it’s meant to add power to the process and a further layer of low-cost protection against contamination." Goddard’s collaborators on this project include UMass Amherst food scientist Lynne McLandsborough and Joe Hotchkiss, director of the Michigan State University School of Packaging.

Provided by University of Massachusetts Amherst (news : web)

Hershey scientists improve methods for analysis of healthful cocoa compounds

 Two scientific publications report on improved methods for determining the amounts of flavanol antioxidants in cocoa and chocolate. The research, sponsored by The Hershey Center for Health and Nutrition, was a collaboration between scientists at The Hershey Company and other scientific laboratories.

Scientists at Planta Analytica (Danbury, CT) isolated and separated cocoa flavanol antioxidants on a large scale. The Hershey scientists and collaborating scientists at the Pennsylvania State University-M.S. Hershey Medical Center (Hershey, PA) teamed up to determine the purity of these flavanols by HPLC and by Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectroscopy. The isolated compounds were then used as standards in the determination of flavanol cocoa antioxidants in a cocoa powder and a dark chocolate.

"We believe this represents the first large scale purification of standards for flavanol antioxidant determination" said Dr. Jeffrey Hurst of the Hershey Center for Health and Nutrition. "Prior to this, only dimers were commercially available. With a full series of standards, our flavanol determinations are not only more accurate, but the values are much higher, between 40% to 100% higher, than previously published methods using proprietary standards." This also means that standards are commercially available to various laboratories. This collaborative work was published in the online journal

In other research published in the Journal Association of Official Analytical Chemists, scientists from The Hershey Company and Brunswick Laboratories (Newton, MA) reported on the development of a new method for determining total procyanidins. This method is a colorimetric test based on the specific reaction of dimethylaminocinnamaldehyde (DMAC) with flavanols. The method measures flavanol monomers, including EGCG, as well as higher flavanol polymers. The method which is standardized using a commercially available flavanol dimer, was validated at two Brunswick Laboratories facilities and at Hershey with all three laboratories providing comparable results at the 95% confidence level. "The specific reaction of DMAC with the flavanols has been known since the 1950s. This method is a simple and quick way to measure total procyanidins in cocoa and chocolate" said Dr. Mark Payne of the Hershey Center for Health and Nutrition. "Compared to the HPLC method, which separates individual compounds, this method gives one number, which importantly includes polymers of flavanols beyond ten."

"These reports are part of an ongoing series of publications, by Hershey and its collaborators, designed to improve upon the methods to determine flavanol antioxidants from cocoa and chocolate," said Dr. David Stuart, of the Hershey Center for Health and Nutrition. "We want to make these methods generally available to the chocolate industry initially, with the intent of having uniformly agreed upon methods of determining the level of these important molecules."

These new methods can be used in research and other applications involving dietary intake of cocoa and chocolate, clinical interventions and food standardization".

Provided by The Hershey Company

Lithium-ion battery with new chemistry could power electric vehicles

While car companies race to develop electric and hybrid electric vehicles, one of the biggest challenges they face is finding a suitable energy storage system. Lithium-ion batteries, which currently power a variety of smaller consumer electronics devices, could ideally fill this role. But at the moment, they require further improvements in terms of energy density and power density in order to be used effectively in electric vehicles. Now in a new study, researchers have developed a novel type of lithium-ion battery with an anode and cathode that involve new, advanced battery chemistries, greatly improving the battery’s performance and likely making it suitable for electric vehicles.

The researchers, Jusef Hassoun, Ki-Soo Lee, Yang-Kook Sun, and Bruno Scrosati, from the University of Rome Sapienza in Rome, Italy, and Hanyang University in Seoul, South Korea, have published their study on the advanced lithium-ion battery in a recent issue of the Journal of the American Chemical Society.

Their study builds on the team’s previous research involving the development of novel, advanced lithium-ion battery chemistries. The key to the high performance lies in the battery’s electrode materials. Here, the scientists use a tin-carbon anode and a cathode made of lithium manganese oxide doped with nickel and cobalt. As far as the researchers know, a lithium-ion battery with this unique electrode combination has never been reported before.

“The battery is based on a new combination between a high-voltage cathode and a nanostructured anode material,” Scrosati told PhysOrg.com. “The battery operates with a very stable capacity at high discharge rates with no significant capacity losses throughout the entire cycling test.”

The new electrode materials provide certain advantages for the overall battery. As the researchers previously demonstrated, the tin-carbon anode has a high cycling life of several hundred cycles without a reduction in capacity, as well as discharge-charge efficiency approaching 100%. By applying a surface treatment to the anode, the researchers could further improve the capacity.

As for the new manganese-based cathode materials, they are more abundant, less expensive, more environmentally friendly, and have a higher stability at low temperatures compared to the lithium cobalt oxide cathode used in conventional lithium-ion batteries. Also, in designing the new cathode, the researchers carefully optimized the composition, particle size, shape, morphology, and tap density.

“The battery has: 1) a high volumetric and gravimetric energy density; 2) a high rate capability due to the nano-structured characteristics of the electrode materials; 3) an excellent cycle life; and 4) low cost, due to the use of electrode materials based on abundant elements,” Scrosati said.

The cathode’s high voltage and high capacity provides the new battery with a higher energy density (170 Wh/kg at average discharge voltage of 4.2 volts) than conventional lithium-ion batteries.

“The conventional lithium-ion batteries have an energy density of about 120-150 Wh/kg, depending on the used cathode material,” Scrosati said. “Generally, commercial lithium battery cells using layer structure cathode materials, for instance, NCA and NMC, deliver from 100 to 150 Wh/kg.”

Altogether, the high energy density, stable cycle life, and high rate capacity suggest that the battery looks very promising for powering electric vehicles.

“In summary, with respect to those using conventional lithium-ion batteries, electric vehicles using our battery may assure: 1) a longer driving range (210 km/charge vs. 150 km/charge due to the higher energy density; 2) a higher top speed; 3) a lower cost; and 4) better overall performance especially at low temperatures,” Scrosati said.

More information: Jusef Hassoun, et al. “An Advanced Lithium Ion Battery Based on High Performance Electrode Materials.” Journal of the American Chemical Society. DOI:10.1021/ja110522x