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CNIO researchers discover a new regulator of drug detoxication
Public release date: 11-Oct-2013 [
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Contact: Nuria Noriega comunicacion@cnio.es Centro Nacional de Investigaciones Oncologicas (CNIO)
The CNIO group led by researcher Erwin Wagner discovered that the Fra-1 protein is causally involved in liver fibrosis and protects the liver from drug-induced liver damage
Drug abuse and alcohol are some of the most frequent causes of liver damage, particularly in developed countries. Such kind of liver damage can cause irreversible liver failure and even cancer. Researchers from the Spanish National Cancer Research Centre (CNIO) have discovered an important new protective role of the Fra-1 protein, which neutralizes the damage caused by agents, such as the analgesic drug acetaminophen (Paracetamol). This is the first study to reveal a function of Fra-1 in protecting this important organ. The study is published today in the journal Hepatology.
The journal includes a comment by David A. Brenner, from the University of California, who is a leader in the field of gastroenterological research, specializing in diseases of the liver. In the comment, Brenner highlights the importance of this study, saying that it "should provide new insights into the complex role of AP-1 [a family of proteins which Fra1 is part of] in liver disease and the potential role of inhibitors of the signalling pathway in the treatment of specific liver diseases."
A NEW 'SUPER-DETOXIFYING' MOUSE
Key to the study has been a new 'super-detoxifying' mouse model generated by the team around Erwin Wagner, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme and holder of an ERC Advanced Grant.
"Our mouse was designed to produce extra Fra-1 protein only in the liver, which allowed us to study its specific function in this organ and thus eliminate side effects that an excess of protein might have in other tissues", explains Sebastian Hasenfuss, first author of the study.
According to the article, increased production of Fra-1 in the liver of these mice protects the organ from damage caused by drugs, such as Paracetamol. Moreover, Erwin Wagner's team also found that the removal of Fra-1 in mice causes a significant increase in liver damage.
How Fra-1 protects the liver is another question that Wagner's team answers in the article. On one hand, Fra-1 stimulates genes related to the glutathione defence system against free radicals and thus avoids cellular damage. On the other hand, Fra-1 stimulates genes that cause the removal of toxins from the body.
These results bring to light a new molecular component that could be key in future studies searching for new drugs for diseases related to the accumulation of toxic compounds, such as acute liver disease, alcoholism or cancer.
The team also highlights the importance that Fra-1's detoxifying role might have in the generation of chemotherapy resistance: "Tumour cells use very similar mechanisms as Fra-1 to eliminate chemotherapeutic agents", says Wagner, concluding that: "This makes us think that tumours might use Fra-1 to generate chemotherapy resistance and thus be able to keep growing."
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Reference article:
The AP-1 transcription factor Fra-1 is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism. Hasenfuss SC, Bakiri L, Thomsen MK, Hamacher R, Wagner EF. Hepatology (2013). doi: 10.1002/hep.26518
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
CNIO researchers discover a new regulator of drug detoxication
Public release date: 11-Oct-2013 [
| E-mail
| Share
]
Contact: Nuria Noriega comunicacion@cnio.es Centro Nacional de Investigaciones Oncologicas (CNIO)
The CNIO group led by researcher Erwin Wagner discovered that the Fra-1 protein is causally involved in liver fibrosis and protects the liver from drug-induced liver damage
Drug abuse and alcohol are some of the most frequent causes of liver damage, particularly in developed countries. Such kind of liver damage can cause irreversible liver failure and even cancer. Researchers from the Spanish National Cancer Research Centre (CNIO) have discovered an important new protective role of the Fra-1 protein, which neutralizes the damage caused by agents, such as the analgesic drug acetaminophen (Paracetamol). This is the first study to reveal a function of Fra-1 in protecting this important organ. The study is published today in the journal Hepatology.
The journal includes a comment by David A. Brenner, from the University of California, who is a leader in the field of gastroenterological research, specializing in diseases of the liver. In the comment, Brenner highlights the importance of this study, saying that it "should provide new insights into the complex role of AP-1 [a family of proteins which Fra1 is part of] in liver disease and the potential role of inhibitors of the signalling pathway in the treatment of specific liver diseases."
A NEW 'SUPER-DETOXIFYING' MOUSE
Key to the study has been a new 'super-detoxifying' mouse model generated by the team around Erwin Wagner, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme and holder of an ERC Advanced Grant.
"Our mouse was designed to produce extra Fra-1 protein only in the liver, which allowed us to study its specific function in this organ and thus eliminate side effects that an excess of protein might have in other tissues", explains Sebastian Hasenfuss, first author of the study.
According to the article, increased production of Fra-1 in the liver of these mice protects the organ from damage caused by drugs, such as Paracetamol. Moreover, Erwin Wagner's team also found that the removal of Fra-1 in mice causes a significant increase in liver damage.
How Fra-1 protects the liver is another question that Wagner's team answers in the article. On one hand, Fra-1 stimulates genes related to the glutathione defence system against free radicals and thus avoids cellular damage. On the other hand, Fra-1 stimulates genes that cause the removal of toxins from the body.
These results bring to light a new molecular component that could be key in future studies searching for new drugs for diseases related to the accumulation of toxic compounds, such as acute liver disease, alcoholism or cancer.
The team also highlights the importance that Fra-1's detoxifying role might have in the generation of chemotherapy resistance: "Tumour cells use very similar mechanisms as Fra-1 to eliminate chemotherapeutic agents", says Wagner, concluding that: "This makes us think that tumours might use Fra-1 to generate chemotherapy resistance and thus be able to keep growing."
###
Reference article:
The AP-1 transcription factor Fra-1 is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism. Hasenfuss SC, Bakiri L, Thomsen MK, Hamacher R, Wagner EF. Hepatology (2013). doi: 10.1002/hep.26518
[
| E-mail
| Share
]
AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Two days on from his incredible, four-goal performance, capped with the early frontrunner for goal of the year, the hockey world is still buzzing about nineteen-year-old sensation Tomas Hertl. But on Thursday, the conversation took a slight turn when Washington Capitals' coach Adam Oates gave voice to a growing crowd of dissenters, calling Hertl's move disrespectful.
And that's when Joe Thornton came to Hertl's rescue. Sensing that the conversation was beginning to turn against his linemate, the Sharks' captain decided to do his captainly duty Thursday, turning the attention away from Tomas Hertl and squarely on himself.
How did he do that? He whipped out one doozy of a quote. From Jason Botchford of The Province:
Hearing a question to Marleau about Hertl and whether he was showboating, Thornton said: “Shut up, have you ever played the game?”
When the press turned his way, he then added:
“I’d have my [rooster] out if I scored four goals. I’d have my [rooster] out, stroking it.”
In Hertl's defense, he's new to this country. That's a good way to get deported.
But seriously, oh my God. Thornton can't possibly have actually said that, can he? David Pollak?
Well then.
Yeah, we can probably safely assume that Joe Thornton didn't expect to be quoted. But he was. And now here we are.
Amazingly, Thornton's never had a four-goal game. He's at nearly a point a game over his lengthy NHL career, racking up 1120 points in 1128 games with his mad dangles, and he's registered four career hat tricks, the most recent of which came October 27, 2010 versus the New Jersey Devils. But he's never dropped four on an opponent. Which is why he's never dropped trou on an opponent.
When he does, though, well, if you thought Hertl's between-the-legs move was over the top, just wait for Jumbo Joe's to rock out on his fourth tally of the night. It'll bring new meaning to the term "junk goal".
There's a reason that Topeak's MiniRocket iGlow bike bump won a 2013 Red Dot Design Award: the transparent barrel encases a internal optical fiber that turns a small red LED into a brilliantly-visible glowing safety strip. And at just 67 grams, it adds minimal weight to your bike's frame, so it's easy to always keep on hand. A pair of watch-sized batteries powers it continuously for up to 50 hours on its brightest setting, and 100 hours when dimmed.
Nissan's just pulled the covers off its fancifully styled ZEOD RC race car that may eventually hit speeds of up to 300km/h (about 185mph). Though the acronym stands for "zero emissions, on demand," the vehicle could end up being a hybrid model that switches between gas and EV modes (as opposed to a pure electric car) by the time it hits Le Mans in 2014. Regardless, the company's Nismo racing division (creator of the all-electric Nismo RC) plans to enter it in the so-called Garage 56 class of the famed race, reserved for vehicles that showcase breakthrough technology. While the company flaunted the design at Circuit de la Sarthe in France today, the car won't start trials until later this summer, after which the final drivetrain will be chosen. Prior to hitting the track, though, it'll have its work cut out just to top Toyota's P001, the current EV lap-speed champ.
HOUSTON (AP) ? Ex-Enron Corp. CEO Jeffrey Skilling ? seen by many as exemplifying the worst in corporate fraud and greed in America ? could be released from prison in about four years after a federal judge on Friday shaved off a decade from his original sentence of more than 24 years.
Skilling's resentencing during a packed courtroom hearing brought one of the country's most notorious financial scandals ? the collapse of the once-mighty energy giant ? to a conclusion that upset some former Enron workers.
Ex-Enron worker Diana Peters, the only victim who spoke at the resentencing hearing, said afterward in a phone interview that Skilling should have to serve his entire original sentence.
"Jeffrey Skilling has never taken any responsibility for his actions," said the 63-year-old Peters, who lives in Huntsville, north of Houston. "He has no remorse for the end result of what happened."
Even before Friday's resentencing, which was part of a court-ordered reduction and a separate agreement with prosecutors, Skilling had already been set to have his sentence of about 8? years shortened after an appeals court vacated his original sentence by U.S. District Judge Sim Lake.
The appeals court ruled that a sentencing guideline was improperly applied. However, Skilling's resentencing was delayed for years as he unsuccessfully sought to overturn his convictions, including appealing to the U.S. Supreme Court.
The Justice Department said in order to resolve a case that's gone on for more than 10 years, it agreed to an additional reduction of about 20 months as part of a deal to stop Skilling from filing any more appeals. Federal prosecutors say it will allow for $41.8 million of Skilling's assets to be distributed as restitution to victims of Enron's 2001 collapse.
Skilling, 59, who has been in prison since 2006, declined to make a statement during Friday's hearing.
His attorney, Daniel Petrocelli, said he disagrees with claims that his client, who "still maintains his innocence," never expressed remorse for what happened at Enron. He said Skilling wasn't aware of the illegal activities of others but "took complete responsibility for all the actions" at the company.
Petrocelli said the reduction, combined with time off for good behavior and other factors, means Skilling is likely to be released by 2017.
During the hearing, prosecutor Patrick Stokes criticized Skilling for continuing "to cast himself as a victim" and said Skilling "is anything but a victim."
"Mr. Skilling was not only at the pinnacle of Enron, he was at the pinnacle of the fraud schemes," Stokes said.
Once the money from Skilling's assets is added, about $560 million in restitution will have been collected for victims of the Enron scandal, Stokes said.
Former Enron employee George Maddox said he still blames Skilling for his losing $1.3 million in retirement savings when Enron collapsed. Maddox worked for 30 years as a plant manager with the company.
"Long sentences are for no one but poor people," said Maddox, 79, who lives in the East Texas town of Van and is now supporting his 16-year-old grandson and himself mainly on Social Security income.
Even with the reduced sentence, Skilling's prison term is still the longest of those involved in the Enron scandal. He was the highest-ranking executive to be punished. Enron founder Kenneth Lay's similar convictions were vacated after he died of heart disease less than two months after his trial.
Philip Hilder, a Houston attorney who represented several ex-Enron executives who cooperated with prosecutors, called Skilling's new sentence "a fair resolution" to his case.
But Andrew Stoltmann, a Chicago-based attorney who represented 10 people who lost money in Enron's collapse, called the new sentence "a slap in the face" to ex-Enron workers and investors.
Skilling was convicted in 2006 on 19 counts of conspiracy, securities fraud, insider trading and lying to auditors for his role in the downfall of Houston-based Enron. The company, once the seventh-largest in the U.S., went bankrupt under the weight of years of illicit business deals and accounting tricks.
The U.S. Supreme Court said in 2010 that one of Skilling's convictions was flawed when it sharply curtailed the use of the "honest services" fraud law ? a short addendum to the federal mail and wire fraud statute that makes it illegal to scheme to deprive investors of "the intangible right to honest services."
The high court ruled prosecutors can use the law only in cases where evidence shows the defendant accepted bribes or kickbacks, and because Skilling's misconduct entailed no such things, he did not conspire to commit honest services fraud.
The Supreme Court told a lower court to decide whether he deserved a new trial; the lower court said no.
Enron's collapse put more than 5,000 people out of work, wiped out more than $2 billion in employee pensions and rendered worthless $60 billion in Enron stock. Its aftershocks were felt across Houston and the U.S. energy industry.
___
Follow Juan A. Lozano at http://www.twitter.com/juanlozano70 .
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