ED drugs could protect liver from sepsis damage

Drugs that are on the market to treat erectile dysfunction (ED) could have another use — they might be able to protect the liver from damage caused by sepsis, a systemic inflammatory response to infection, say School of Medicine researchers. They recently published their findings in Science Signaling.

Infection can lead to the release of chemicals that cause whole-body inflammation, which can cause life-threatening damage to organs including the liver and kidneys, explained senior investigator Timothy Billiar, chair of the Department of Surgery. Sepsis is a leading cause of death in the intensive care unit.

“Sepsis is a very challenging problem, so the possibility that we might be able to repurpose a drug that is in use and well understood is very exciting,” Billiar said.

Sepsis triggers production of a protein called tumor necrosis factor, or TNF, which helps fight infection but is harmful at sustained high levels. The researchers found in a mouse model of sepsis that sildenafil, more commonly known as Viagra, induced the liver to produce greater amounts of a protein called cyclic GMP, which in turn led cells to shed surface proteins called TNF receptor, reducing TNF signaling in the cells and preventing  liver damage. Experiments with human liver cells also showed the protective effects of the drug.

“Our study suggests that increasing the bioavailability of cyclic GMP might be beneficial in ameliorating the inflammation associated with sepsis,” Billiar said. “Sildenafil and other ED drugs might be a good approach to try early in the course of the illness to forestall organ damage.”

The research team plans to verify their findings in a large animal model of sepsis.

Other Pitt investigators included lead author Meihong Deng, Patricia A. Loughran, Liyong Zhang and Melanie J. Scott.

The project was funded by National Institutes of Health (NIH).

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NIH grant will help to combat “sitting disease”

Graduate School of Public Health researchers are changing conventional thinking about how to improve the health of sedentary people at risk for diabetes and heart disease in a new study designed to combat a condition called “sitting disease.”

With a $3 million grant from NIH, epidemiology faculty member Andrea Kriska and her team will investigate whether they can improve the health of sedentary, overweight people with a program initially focusing on decreasing the amount of time they spend sitting, rather than starting with an emphasis on increasing the amount of time they spend exercising. This current study will test the concept that sitting less may be as important as participating in planned bouts of moderate-intensity physical activity in sedentary people.

Said Kriska: “To maintain a healthy lifestyle, national recommendations are that you get a minimum of about two-and-a-half hours of moderate to vigorous physical activity every week — but we know that there are a lot of people who do little, if any, physical activity on a regular basis. For those people, getting them to exercise might not be as initially effective as working at the other end of the activity spectrum by trying to decrease the amount of time they spend sitting.”

The grant will be used to create a new, alternate version of the group lifestyle balance (GLB) program, designed for overweight and inactive individuals who want to improve their health. The GLB program was modified for use in public health from the successful lifestyle intervention used in the U.S. diabetes prevention program clinical research trial, which demonstrated for the first time — in sites across the U.S. — that people at risk for diabetes who lost weight and increased their physical activity levels sharply reduced their risk for diabetes and heart disease, outperforming people who took a diabetes drug instead. Developed in Pittsburgh by faculty from public health’s Diabetes Prevention Support Center (DPSC), the GLB has been shown to be effective in a variety of diverse community settings, ranging from the worksite and the military to community senior centers and primary care facilities.

The GLB program involves 22 sessions delivered over the course of one year that focus on healthy lifestyle changes, including encouraging people to slowly and safely increase their levels of physical activity. The program introduces the idea of reducing sedentary behavior toward the end of the sessions, with the major emphasis on increasing physical activity levels throughout the program.

The new grant will put the concept of sitting less as the primary movement goal.

Said co-investigator M. Kaye Kramer, epidemiology faculty member and director of the DPSC: “At the beginning, participants are not going to start tracking how much walking and biking they do. Instead, they’re going to think about how much time they spend sitting — and then start decreasing that time.”

The program will seek to enroll more than 300 people age 50 and older in the Pittsburgh region. Participants will be screened to ensure that they are at risk for diabetes or metabolic syndrome in order to test the program on those most likely to benefit from it. The research team will track participants’ weight, waist circumference, blood glucose and fat levels, blood pressure, physical function, quality of life and, of course, changes in sedentary behavior and physical activity.

“We believe that we’re going to see an increase in overall movement by encouraging people to sit less,” said Kriska. “And that will lead to a whole host of health improvements, from weight loss to decreasing risk factors for diabetes and heart disease.”

Additional Pitt investigators are Bonny Rockette-Wagner, Vincent Arena, Elizabeth Venditti, Rachel Miller, Tom Songer and Jennifer Brach.

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CO2 recycling catalysts & enzymes may aid sustainable energy

Researchers at the Swanson School of Engineering have identified a promising design principle for renewable energy catalysts. Using advanced computational modeling, they found that common laboratory chemicals may play a similar role as biological catalysts that nature uses for efficient energy storage.

The article, “Thermodynamic Descriptors for Molecules That Catalyze Efficient CO2 Electroreductions,” published in ACS Catalysis, was written by John A. Keith, a faculty member and Richard King Mellon Faculty Fellow in Energy in the Department of Chemical and Petroleum Engineering, and Aude Marjolin, a postdoctoral fellow. The research examined thermodynamic energetics of molecules known as aromatic N-heterocycles (ANH), which earlier studies have shown help make CO2 recycling more energetically efficient.

Said Keith: “Sustainable fuels research is immensely challenging because not only do we need to understand how to convert waste molecules like CO2 into something useful, like a fuel, we also need to make the overall process not too expensive or energy-intensive.”

Several studies over the past decade have found that common ANH molecules like pyridinium and imidazolium make CO2 recycling processes much more efficient, but it has been unclear how ANH molecules do this. Keith’s quantum chemistry analysis, completed at the Center for Simulation and Modeling (SaM), found that the same experimental conditions used to transform CO2 also are suitable to transform ANH molecules into new molecules that possess a strikingly similar chemical structure as some well-known biomolecules. Coincidentally, nature uses these biomolecules for efficient energy storage processes.

“Instead of searching for the answer to one question, this chemistry is presenting us with one answer to multiple questions,” said Keith.

The results allow computational scientists now to screen hundreds to thousands of molecules a week on Pitt’s SaM cluster, saving time and resources of others developing CO2 recycling catalysts. New investigations also can branch out to identify other molecules that might be able to play a similar role in other green chemical processes, such as efficient water splitting for renewable hydrogen generation or other energetically efficient routes to produce commodity chemicals in a more sustainable manner.

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Preservation system keeps transplant livers healthier

A new preservation system that pumps cooled, oxygen-rich fluid into donor livers not only keeps the organs in excellent condition for as long as nine hours before transplantation, but also leads to dramatically better liver function and increases survival of recipients, according to a series of animal studies by researchers at the School of Medicine and the McGowan Institute for Regenerative Medicine. The system could be tested with transplant patients at UPMC later this year.

The findings, published online in the American Journal of Transplantation, suggest that it’s possible to use the technique of “machine perfusion” with a newly created cell-free oxygenated solution to expand the number of high-quality livers available for transplant, thereby shortening waiting times and reducing patient mortality.

Currently, 20-40 percent of donor livers cannot be transplanted into recipients because oxygen deprivation during storage and transport in conventional containers can make pre-existing tissue damage worse. If the damage is too extensive, the organ cannot be safely transplanted into a patient.

Said senior investigator Paulo Fontes, surgery faculty member in medicine, UPMC transplant surgeon at the Starzl Transplantation Institute and deputy director of the McGowan Institute: “Standard practice is to use a method called cold static preservation, which uses tissue cooling to slow down metabolism with the aim of reducing the demand for oxygen and thus protecting cells from death. In our new system, we pump a special fluid designed to deliver oxygen to the liver, creating an environment that supports normal function. The integrity of the cells and vital metabolic activity is sustained for eventual transplantation of the organ.”

The research team optimized a machine-perfusion (MP) device that was developed by Organ Assist in the Netherlands, and added a fluid with a hemoglobin-oxygen carrier component to deliver high concentrations of oxygen to the tissue. The liver is immersed in chilled fluid, which also is pumped through tubes inserted into the organ’s large blood vessels to effectively oxygenate the tissue.

The team transplanted six pigs with livers that had been kept for nine hours, roughly the average time between recovery of the organ and transplantation into a recipient, in the MP system and another six with organs placed in the standard container.

They found that 100 percent of the pigs that got MP livers survived, compared to 33 percent of those who received conventionally preserved organs. The MP livers functioned better, produced more bile and had higher oxygen levels than their conventional counterparts, and analyses of multiple biomarkers including inflammatory mediators indicated that the MP livers had been better preserved.

“It was immediately obvious to us that the pigs who received MP livers looked much healthier and easily moved around their pens just hours after they woke up from the surgery,” Fontes said. “They didn’t look as ill as the animals treated with standard cold preservation.”

The data from the studies has been shared with federal regulators, he added, with the aim of launching a clinical trial to test the system at UPMC this year.

“This system has great potential to enhance our current standards for organ preservation, which should translate into more patients getting a life-saving procedure with potentially better outcomes,” Fontes said. “Not only that, we have hopes of a faster recovery because the liver could be less likely to become injured due to a lack of oxygen.”

Pitt co-investigators included Roberto Lopez, Yoram Vodovotz, Marta Minervini, Victor Scott, Kyle Soltys, Sruti Shiva, Shirish Paranjpe, David Sadowsky, Derek Barclay, Ruben Zamora, Donna Stolz, Anthony Demetris, George Michalopoulos and James Wallis Marsh, with a colleague from Organ Assist.

The study was funded by Mr. and Mrs. Garcia de Souza and NIH.

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Black students are not less engaged in school, study says

James Huguley, research associate in the School of Social Work and the Center on Race and Social Problems, has published a new study that takes on the popular perception that African-American students are less engaged in school than white students.

Using a sample of nearly 25,000 black and white middle and high school students from across the country, Huguley and a colleague from the University of Wisconsin-Madison demonstrate that most observed racial differences in school-related attitudes and behaviors, which they collectively call “academic orientations,” are almost entirely attributable to differences in family background and resources, not race.

Said Huguley: “Although it’s sometimes popular to believe that black kids care less about school, independent of family resources we see that across races, attitudes and behaviors related to achievement are fairly similar.”

In fact, their findings demonstrate that when socioeconomic factors are accounted for, African-American students actually hold slightly more positive academic orientations than do their white counterparts from comparable backgrounds. These findings were not substantially affected by school racial composition, suggesting that these similarities in academic orientations hold across many school contexts in the United States.

for racial achievement gaps in adolescence at all, and where they do, they serve to work in favor of African Americans, although very slightly. He suggests instead that the field would be much better served by examining early learning experiences rather than perceived differences in teenagers’ attitudes toward schools.

The study was published in Social Forces.

—Compiled by Marty Levine

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