Honeybee Venom Induced 100% Cancer Cell Death in Lab studies

A specific concentration of honeybee venom can induce 100% cancer cell death, while having minimal effects on normal cells.

“We found that melittin can completely destroy cancer cell membranes within 60 minutes.”

#melittin #honeybeevenom #cancer

Ciara Duffy, Anabel Sorolla, Edina Wang, Emily Golden, Eleanor Woodward, Kathleen Davern, Diwei Ho, Elizabeth Johnstone, Kevin Pfleger, Andrew Redfern, K. Swaminathan Iyer, Boris Baer, Pilar Blancafort. Honeybee venom and melittin suppress growth factor receptor activation in HER2-enriched and triple-negative breast cancer. npj Precision Oncology, 2020; 4 (1) DOI: 10.1038/s41698-020-00129-0

Scientists reverse fibrosis in preclinical studies – Lung and Liver

Scientists reverse fibrosis in preclinical studies – Lung and Liver

The publication reports on a new target: a dopamine receptor. The authors found that the receptor is unique to lung and liver fibroblasts. Stimulating it blocks YAP and TAZ, reducing and reversing the growth and scar-forming abilities of fibroblasts. Stimulating the dopamine receptor in fibroblasts appeared to switch them from a matrix-depositing state that supports fibrosis to a matrix-degrading state that supports resolution or reversal of fibrosis. In lung and liver fibrosis models, the approach reversed the fibrotic process in these organs.

#fibrosis #dopamine #treatment

Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis: ANDREW J. HAAK, ENIS KOSTALLARI, DELPHINE SICARD, GIOVANNI LIGRESTI, KYOUNG MOO CHOI, NUNZIA CAPORARELLO, DAKOTA L. JONES, QI TAN, JEFFREY MERIDEW, ANA M. DIAZ ESPINOSA, AJA ARAVAMUDHAN, JESSICA L. MAIERS, RODNEY D. BRITT, JR., ANJA C. RODEN, CHRISTINA M. PABELICK, Y. S. PRAKASH, SEYED MEHDI NOURAIE, XIAOYUN LI, YINGZE ZHANG, DANIEL J. KASS, DAVID LAGARES, ANDREW M. TAGER, XARALABOS VARELAS, VIJAY H. SHAH, DANIEL J. TSCHUMPERLIN Science Translational Medicine 30 Oct 2019: Vol. 11, Issue 516, eaau6296 DOI: 10.1126/scitranslmed.aau6296

https://stm.sciencemag.org/content/11/516/eaau6296

Rage Video

https://www.youtube.com/watch?v=Y9AQ1hYvnx4&t=4s

Hepatitis B viruses cured – Pilot Study

Hepatitis B viruses cured – Pilot Study

Researchers have for the first time succeeded in conquering a chronic infection of the hepatitis B virus in a mouse model. The team showed in its publication, that T-cell therapy can provide a permanent cure. #hbv #hepatitisb #cure Karin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Lütgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, Ulrike Protzer. T cell receptor grafting allows virological control of hepatitis B virus infection. Journal of Clinical Investigation, 2019; DOI: 10.1172/JCI120228 https://www.jci.org/articles/view/120228

Nitrate Rich foods may prevent Fatty Liver Disease

Nitrate Rich foods may prevent Fatty Liver Disease

“When we supplemented with dietary nitrate to mice fed with a high-fat and sugar Western diet, we noticed a significantly lower proportion of fat in the liver,” says Mattias Carlström, Associate Professor at the Department of Physiology and Pharmacology, Karolinska Institutet. Their results were confirmed by using two different cell culture studies in human liver cells. Apart from a lower risk of steatosis, the researchers also observed reduction of blood pressure and improved insulin/glucose homeostasis in mice with type 2 diabetes. Isabel Cordero-Herrera, Mikael Kozyra, Zhengbing Zhuge, Sarah McCann Haworth, Chiara Moretti, Maria Peleli, Mayara Caldeira-Dias, Arghavan Jahandideh, Han Huirong, Josiane de Campos Cruz, Andrei L. Kleschyov, Marcelo F. Montenegro, Magnus Ingelman-Sundberg, Eddie Weitzberg, Jon O. Lundberg, and Mattias Carlstrom PNAS published ahead of print December 17, 2018 https://doi.org/10.1073/pnas.1809406115

Nutmeg’s hidden power: Helping the liver

Nutmeg’s hidden power: Helping the liver

Nutmeg’s hidden power: Helping the liver

Nutmeg is the seed of the Myristica fragrans tree, which is commonly found in Indonesia, and has been used to treat asthma, rheumatic pain, toothaches and infections. In the laboratory, researchers have shown that nutmeg can fight hyperlipidaemia, hyperglycemia, heart tissue damage and hepatotoxicity. Inspired by these studies, Xiu-Wei Yang, Frank Gonzalez, Fei Li and colleagues wanted to see how nutmeg prevents damage to the liver.

Citation: PPARα Mediates the Hepatoprotective Effects of Nutmeg Xiao-Nan Yang, Xue-Mei Liu, Jian-He Fang, Xu Zhu, Xiu-Wei Yang, Xue-Rong Xiao, Jian-Feng Huang, Frank J. Gonzalez, and Fei Li Journal of Proteome Research 2018 17 (5), 1887-1897

DOI: 10.1021/acs.jproteome.7b00901

Nutmeg, acylcarnitines, PPAR, myrislignan, liver, peroxisome proliferator-activated receptor alpha, hyperlipidaemia, hyperglycemia, heart tissue damage, hepatotoxicity

Indian spice may delay liver damage and cirrhosis

2010 study posted for filing
Contact: Emma Dickinson
edickinson@bmjgroup.com
44-207-383-6529
BMJ-British Medical Journal

Curcumin improves sclerosing cholangitis in Mdr2 -/- mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation

Curcumin, one of the principal components of the Indian spice turmeric, seems to delay the liver damage that eventually causes cirrhosis, suggests preliminary experimental research in the journal Gut.

Curcumin, which gives turmeric its bright yellow pigment, has long been used in Indian Ayurvedic medicine to treat a wide range of gastrointestinal disorders.

Previous research has indicated that it has anti-inflammatory and antioxidant properties which may be helpful in combating disease.

The research team wanted to find out if curcumin could delay the damage caused by progressive inflammatory conditions of the liver, including primary sclerosing cholangitis and primary biliary cirrhosis.

Both of these conditions, which can be sparked by genetic faults or autoimmune disease, cause the liver’s plumbing system of bile ducts to become inflamed, scarred, and blocked. This leads to extensive tissue damage and irreversible and ultimately fatal liver cirrhosis.

The research team analysed tissue and blood samples from mice with chronic liver inflammation before and after adding curcumin to their diet for a period of four and a period of eight weeks.

The results were compared with the equivalent samples from mice with the same condition, but not fed curcumin.

The findings showed that the curcumin diet significantly reduced bile duct blockage and curbed liver cell (hepatocyte) damage and scarring (fibrosis) by interfering with several chemical signalling pathways involved in the inflammatory process.

These effects were clear at both four and eight weeks. No such effects were seen in mice fed a normal diet.

The authors point out that current treatment for inflammatory liver disease involves ursodeoxycholic acid, the long term effects of which remain unclear. The other alternative is a liver transplant.

Curcumin is a natural product, they say, which seems to target several different parts of the inflammatory process, and as such, may therefore offer a very promising treatment in the future.

 

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Quercetin blocks hepatitis C infection

Contact: Kim Irwin kirwin@mednet.ucla.edu 310-206-2805 University of California – Los Angeles Health Sciences

Natural compound blocks hepatitis C infection

Finding may lead to a new treatment

Researchers have identified two cellular proteins that are important factors in hepatitis C virus infection, a finding that may result in the approval of new and less toxic treatments for the disease, which can lead to liver cancer and cirrhosis.

An estimated 270 to 300 million people worldwide are infected with hepatitis C and the conventional treatments – interferon and ribavirin – can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, said Samuel French, an assistant professor of pathology and senior author of the study.

French and his team set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP 70 was previously known to be involved, but HSP 40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.

“This is an important finding because we can block these proteins with the idea of reducing the level of the virus in people and, ideally, completely eliminate it,” said French, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center.

The study appeared in the most recent issue of the journal Hepatology.

Since Quercetin has been shown to inhibit hepatitis C infection, French said, a Phase I clinical trial will be launched at UCLA to determine if the compound is safe and effective.

Quercetin is a plant-derived bioflavonoid, and is used by some people as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Currently, there are early-stage clinical trials testing quercetin for safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes.

“Because Quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral resistance,” French said. “Cellular proteins cannot change like viral proteins can.”

Many patients in the United States have a type of hepatitis C virus that does not respond to the standard treatments. In these cases, if the virus can’t be blocked, end-stage liver disease and, ultimately, death may occur. Once HSP 40 and 70 were identified, French and his team used Quercetin in an attempt to block the proteins and found that the compound “reduced infectious particle production at non-toxic concentrations,” according to the study.

“Quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce virus production with low associated toxicity,” the study states.

The UCLA clinical trial will most likely target those with type 1 hepatitis C, which is the non-responsive type prevalent in this country. Only about 50 percent of those with type 1 hepatitis C respond to treatment, French said.

Volunteers with type 1 hepatitis C who opt not to undergo conventional therapies would be recruited for the study. In other studies in other diseases, Quercetin has resulted in no significant side effects, French said.

“A non-toxic treatment for chronic hepatitis C would be great because our current therapies have significant side effects and only a certain percentage of the patient population responds,” French said.

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The three-year study was funded by the National Institutes of Health, the Cure Digestive Diseases Research Center and the Stein Oppenheimer Endowment Award.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

SAMe ( S-adenosylmethionine ) is Effective in Preventing Formation of Primary Liver Cancer in Rats

2009 study posted for filing

A new study investigated the effectiveness of S-adenosylmethionine (SAMe) in the prevention and treatment of hepatocellular carcinoma (HCC) or primary liver cancer. SAMe, a widely available nutritional supplement, with little known side effects, was found to be effective in preventing the formation of HCC in rats. However, high enough levels of SAMe were not attainable to successfully treat established HCC. The findings are available in the August issue of Hepatology, a journal published by John Wiley & Sons on behalf of the American Association for the Study of Liver Diseases.

HCC is the fifth most common cancer and the third most frequent cause of cancer death worldwide. Risk factors for HCC include chronic infection with hepatitis B virus, hepatitis C virus (HCV), dietary aflatoxin, excessive alcohol use, cigarette smoking, diabetes and obesity. The overall 5-year survival for HCC patients is less than 10% and the disease rate is expected to rise due to the high prevalence of HCV in many areas of the world.

Shelly Lu, M.D., of the Keck School of Medicine at the University of Southern California, and colleagues studied the effects of SAMe on chemoprevention and treatment of HCC. In the U.S. the incidence of HCC doubled from 1979 to 1995 and the number of HCC cases for the following 20 to 30 years is projected to increase. “Given these projections, there is a tremendous interest in developing effective chemoprevention strategies,” said Dr. Lu. “And an important property of SAMe that makes it an attractive agent for chemoprevention and treatment of HCC is its ability to selectively kill liver cancer cells,” she added.

During the study researchers injected H4IIE cells into rats and found a 1cm tumor developed in the liver two weeks after injection. A regimen of IV SAMe was started one day after injecting the cells and continued for ten days. The researchers monitored the animals using MRI, ultrasound, and visual inspection to assess the liver tumors. “Treatment with IV SAMe by continuous infusion significantly reduced the tumor size and significantly prevented tumor development after 11 days,” researchers discovered.

Researchers found that if SAMe infusion was started after sizable tumors had already formed it failed to reduce the rate of tumor growth after 24 days of treatment. This is because of a compensatory response of the liver to metabolize SAMe and prevent its accumulation. “The observation that SAMe failed to exert any therapeutic effect in already established HCC is disappointing,” said Dr. Lu. “But whether SAMe can be effective in treating HCC in man remains unclear because this compensatory mechanism may not work properly in human HCC. Nevertheless, effectiveness of SAMe in chemoprevention of human HCC deserves study now.”

Long-term L-carnitine supplementation prevents development of liver cancer

2009 study posted for filing

Contact: Lin Tian
wjg@wjgnet.com
86-105-908-0039
World Journal of Gastroenterology

A study will be published on March 21, 2009 in World Journal of Gastroenterology addresses the question. A research group in King Saud University, Kingdom of Saudi Arabia investigated, for the first time, the role of carnitine, a naturally occurring compound that is synthesized mainly in the liver, during the development of hepatocarcinogenesis. Authors of the study reported that carnitine deficiency is a risk factor and should be viewed as a mechanism in hepatic carcinogenesis, and that long-term L-carnitine supplementation prevents the development of liver cancer. Therefore, carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.

Chemoprevention is defined as the use of naturally occurring and/or synthetic compounds in cancer therapy in which the occurrence of cancer can be entirely prevented, slowed or reversed. L-carnitine is a naturally occurring compound which is primarily located in mitochondria and possesses potential protective effects against many mitochondrial toxic agents. It is derived from two sources; endogenous synthesis, in the liver and kidney, and from exogenous dietary sources such as red meat and dairy products. L-carnitine is an essential cofactor for the translocation of long chain fatty acids from the cytoplasmic compartment into mitochondria, where beta-oxidation enzymes are located for ATP production. Despite the liver being the main organ responsible for endogenous synthesis of L-carnitine, we were unable to find any studies investigating the role of long-term endogenous carnitine depletion and/or carnitine deficiency during induction of hepatic carcinogenesis.

The research team by Professor Sayed-Ahmed from College of Pharmacy, King Saud University used an experimental model of hepatocarcinogenesis under conditions of carnitine depletion and carnitine supplementation.

In the carnitine-depleted rat model, there were a progressive increase in the activities of liver enzymes as well as massive degenerative changes and evidence of pre-neoplastic lesions in liver tissues including clusters of hepatocytes with atypia and an increased proliferative rate, diffuse bridging fibrosis and nodule formation, bile ducts with marked reactive atypia showing nuclear enlargement, high nuclear/cytoplasmic ratio and prominent nucleoli. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes compared to normal values, as well as normal liver histology with unremarkable central vein and no evidence of pre-neoplastic lesions in liver tissues.

Due to the fact that liver cancer is one of the major health problems in the world and a large sector of patients seek medical attention at a relatively late stage which increases the cost of treatment, King Saud University granted Prof. Sayed-Ahmed and his colleagues a research project with the following specific aims: (1) to understand the possible molecular mechanisms whereby carnitine deficiency provokes hepatic carcinogenesis. (2) to understand the relationship between hepatic cancer and its resistance to cancer chemotherapy, and (3) to gain knowledge on the possible mechanisms by which carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.

 

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Reference: Al-Rejaie SS, Aleisa AM, Al-Yahya AA, Bakheet SA,Alsheikh A, Fatani AG, Al-Shabanah OA, Sayed-Ahmed MM. Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats World J Gastroenterol 2009; 15(11): 1373-1380 http://www.wjgnet.com/1007-9327/15/1373.asp

Correspondence to: Dr. Mohamed M Sayed-Ahmed, Department of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Kingdom of Saudi Arabia. mmsayedahmed@hotmail.comTelephone: +966-506065734 Fax: +966-1-14677200

 

Miracle leaves that may help protect against liver damage: Sea buckthorn (Hippophae rhamnoides)

Contact: Meral Nugent
meral.nugent@soci.org
020-759-81533
Society of Chemical Industry

Sea buckthorn (Hippophae rhamnoides) berries are well known for their cholesterol busting properties, but scientists in India say that its leaves are also rich in anti-oxidants and may help ward off liver disease, according to new research due to be published in the Society of Chemical Industry’s (SCI) Journal of the Science of Food and Agriculture.

Indigineous to the mountainous regions of China and Russia, sea buckthorn has been shown to be rich in vitamin C, vitamin E, flavonoids and essential fatty acids. The leaves are also used to make a tea.

In a clinically controlled study, scientists looked at whether the leaves had any protective effects by testing a group of rats, some of whom were given the leaf extract before being administered with a liver damage agent, carbon tetrachloride (CCI4).

Six groups were looked at in all – group 1 was given a daily dose of saline for 5 days; group 2 received saline for 4 days and on the 5th day was given CCI4; group 3 was given a daily dose of silymarin for 5 days followed by a single dose of CCI4; groups 4, 5 and 6 were given 50, 100 and 200mg of sea buckthorn leaf extract respectively for five days followed by a single dose of CCI4 on the 5th day.

The results showed that the leaf extract appeared to confer a protective mechanism on the liver – the rats given CCI4 minus the leaf extract had sustained significant liver damage compared to the control group that did not receive CCI4. In comparison, liver damage was severely restricted in the rats given leaf extract at 100mg and 200mg and CCI4.

 

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For more information or a full copy of the paper, contact: Meral Nugent, Press and Public Relations Manager, T: +44 (0)20 7598 1533, F: +44 (0) 20 7598 1545, Mob: 07931 315077 E

Homeopathic solutions for a global catastrophe: Arsenic remedy for arsenic poisoning?

Reposted at Request and debate 2003 Study

Contact: Gemma Bradley press@biomedcentral.com 44-207-323-0323 BioMed Central

Arsenic remedy for arsenic poisoning?

A homeopathic remedy made from arsenic oxide could ease the suffering of the hundreds of millions of people at risk from arsenic poisoning worldwide.  Research, published this week in BMC Complementary and Alternative Medicine, suggests that Arsenicum Album reduces the liver damage caused by arsenic poisoning.

Arsenic contamination of groundwater is a major health problem for people from India, Bangladesh and at least fifteen other countries. Drinking arsenic contaminated well water has caused the rapid spread of skin diseases and liver damage. Although chemical treatment can remove arsenic contamination, such efforts to provide safe drinking water have not been widely implemented.

In their search to find inexpensive treatments for arsenic poisoning that are easy to administer, effective in low doses and non-toxic, researchers from University of Kalyani, West Bengal, discovered the homeopathic remedy Arsenicum Album yielded positive effects in mice. They now believe the homeopathic treatment can reduce the liver damage in humans caused by arsenic poisoning.

The researchers write: “As supplying arsenic-free drinking water cannot totally rule out the chances of arsenic contamination from other sources, the problem of eradicating arsenic related diseases cannot be addressed through such effort alone. The potentized homeopathic drug Arsenicum Album not only has the ability to help remove arsenic from the body, but these drugs in microdoses appear to have the ability to detoxify the ill-effects produced by arsenic in mice”.

Professor Khuda-Bukhsh, the research team leader said: “An early human clinical trial may be worth pursuing to verify the efficacy of the homeopathic drug on human volunteers living in arsenic infested areas.”

Mice with and without arsenic poisoning were fed by the drop either distilled water, Arsenicum Album, or alcohol that had been through the same preparation procedure as the homeopathic remedy, three times a day. The research team then monitored the activity of two enzymes, ALT and AST, in the blood and liver of the mice, to assess the level of liver damage in these animals. As both enzymes are more active in mice with arsenic poisoning, their activity can be used as a marker of toxicity. They found that Arsenicum Album, at two different dilutions, could reduce the activity levels of the two enzymes within 72 hours, and maintained its positive effects for up to 30 days. Distilled water had no effect on either enzyme, and alcohol alone actually increased the activity of AST.

The authors write: “It is quite amazing that such microdoses of a potentized homeopathic drug which is produced by the dilution and succession of the toxic substance itself were capable of bringing about such spectacular enzymatic alterations in mice treated with a toxic dose of arsenic oxide. This is more fascinating because the dilution at which the drug appeared to be effective was so high that the chances of even a single original molecule being in them was theoretically almost impossible.”

As the treatment worked in rodents, cynics will not be able to say that this homeopathic remedy works via a psychosomatic effect. The researchers said: “Any attempt to explain the mechanism of action of the homeopathic drug would be highly speculative at the present state of our knowledge – although it could play a role in regulating genes.”

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This press release is based on the following article: Ameliorating effect of microdoses of a potentized homeopathic drug, Arsenicum Album, on arsenic-induced toxicity in mice P Mallick, J Chakrabarti (Mallick), B Guha and AR Khuda-Bukhsh BMC Complementary and Alternative Medicine, 2003 3:7 http://www.biomedcentral.com/1472-6882/3/7  Published 22 October 2003

Upon publication this article will be available online without charge as per BioMed Central’s open access policy. Please include the URL in any report so that your readers can view the full text.

For further information about this research please contact Professor Anisur Rahman Khuda-Bukhsh by email at arkb@klyuniv.ernet.inor by phone on 91-33-2582-8768 (home) or 91-33-2582-8750 extn. 313 or 314 (work)

Alternatively contact Gemma Bradley by email at press@biomedcentral.comor by phone on 44-207-323-0323.

BMC Complementary and Alternative Medicine (http://www.biomedcentral.com/bmccomplementalternmed) is published by BioMed Central (http://www.biomedcentral.com), an independent online publishing house committed to providing immediate free access to peer-reviewed biological and medical research.  This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science.  In addition to open-access original research, BioMed Central also publishes reviews and other subscription-based content

Researchers show that Liver Fibrosis can be stopped, cured and reversed

Contact: Debra Kain ddkain@ucsd.edu 619-543-6163 University of California – San Diego

Modified protein developed by UC-San Diego researchers may lead to first cure for cirrhosis of the liver

University of California, San Diego researchers have proven in animal studies that fibrosis in the liver can be not only stopped, but reversed.  Their discovery, to be published in PLoS Online on December 26, opens the door to treating and curing conditions that lead to excessive tissue scarring such as viral hepatitis, fatty liver disease, cirrhosis, pulmonary fibrosis, scleroderma and burns.

Six years ago, the UC San Diego School of Medicine research team discovered the cause of the excess fibrous tissue growth that leads to liver fibrosis and cirrhosis, and developed a way to block excess scar tissue in mice.  At that time, the best hope seemed to be future development of a therapy that would prevent or stop damage in patients suffering from the excessive scarring related to liver or lung disease or severe burns.

In their current study, Martina Buck, Ph.D., assistant professor of medicine at UCSD and the Veterans Affairs San Diego Healthcare System, and Mario Chojkier, M.D., UCSD professor of medicine and liver specialist at the VA, show that by blocking a protein linked to overproduction of scar tissue, they can not only stop the progression of fibrosis in mice, but reverse some of the cell damage that already occurred.

In response to liver injury – for example, cirrhosis caused by alcohol – hepatic stellate cell (HSC) activated by oxidative stress results in large amounts of collagen.  Collagen is necessary to heal wounds, but excessive collagen causes scars in tissues.  In this paper, the researchers showed that activation of a protein called RSK results in HSC activation and is critical for the progression of liver fibrosis.  They theorized that the RSK pathway would be a potential therapeutic target, and developed an RSK inhibitory peptide to block activation of RSK.

The scientists used mice with severe liver fibrosis – similar to the condition in humans with cirrhosis of the liver – that was induced by chronic treatment with a liver toxin known to cause liver damage. The animals, which continued on the liver toxin, were given the RSK-inhibitory peptide.  The peptide inhibited RSK activation, which stopped the HSC from proliferating.  The peptide also directly activated the caspase or “executioner” protein, which killed the cells producing liver cirrhosis but not the normal cells.

“All control mice had severe liver fibrosis, while all mice that received the RSK-inhibitory peptide had minimal or no liver fibrosis,” said Buck.

Buck explained that the excessive collagen response is blocked by the RSK-inhibitory peptide, but isn’t harmful to the liver.  “The cells continue to do their normal, healing work but their excess proliferation is controlled,” Buck said.  “Remarkably, the death of HSC may also allow recovery from liver injury and reversal of liver fibrosis.”

The researchers found a similar activation of RSK in activated HSC in humans with severe liver fibrosis but not in control livers, suggesting that this pathway is also relevant in human liver fibrosis.  Liver biopsies from patients with liver fibrosis also showed activated RSK.

The study expands on work reported in 2001 in the journal Molecular Cell announcing that a team led by Buck had found that a small piece of an important regulatory protein called C/EBP beta was responsible for fibrous tissue growth, or excessive scar tissue following injury or illness.  When normal scarring goes awry, excessive build-up of fibrous tissue can produce disfiguring scars or clog vital internal organs and lead to serious complications.  Buck and colleagues developed a mutated protein that stopped this excessive fibrous tissue growth.

“Six years ago, we showed a way to prevent or stop the excessive scarring in animal models,” said Buck.  “Our latest finding proves that we can actually reverse the damage.”

Worldwide, almost 800,000 people die from liver cirrhosis each year, and there is currently no treatment for it.  Excessive tissue repair in chronic liver disease induced by viral, toxic, immunologic and metabolic disorders all result in excessive scar tissue, and could benefit from therapy developed from the UCSD researchers’ findings.

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The research was supported by grants from the National Institutes of Health, the Department of Veterans Affairs and UCSD’s Medical Research Foundation.  Buck is the recipient of a Howard Temin Award from the National Cancer Institute.

* Reposted for Filing

Treatment with NAC is associated with better outcomes for children with liver failure

Contact: Amy Molnar amolnar@wiley.com Wiley-Blackwell

Questions remain on NACs true utility for this condition

A new retrospective study on the effects of N-acetylcysteine (NAC) on children with acute liver failure not caused by acetaminophen poisoning has found that the treatment was associated with a shorter hospital stay, higher incidence of liver recovery, and better survival after transplantation. The study is in the January issue of Liver Transplantation, a journal by John Wiley & Sons. The article is also available online via Wiley Interscience (http://www.interscience.wiley.com/journal/livertransplantation).

Acute liver failure in children is rare but can be fatal. Acetaminophen poisoning is a common cause, and is treated with NAC, which acts as an antidote, an anti-inflammatory agent and an antioxidant. One small, uncontrolled study suggested that NAC could also help children with non-acetaminophen induced acute liver failure, leading some medical centers to adopt the treatment.  Recently, researchers led by Christine Kortsalioudaki of King’s College Hospital in London sought to retrospectively evaluate whether NAC is beneficial for those children.

They examined the medical records of 170 children who came to King’s College Hospital with non-acetaminophen induced acute liver failure between 1989 and 2004. Those treated before 1994 were not treated with NAC, while those who came after 1995 did receive NAC. All the children also received standard care to maintain normal tissue oxygenation and prevent and address complications of acute liver failure.

The children who received NAC spent fewer days in intensive care, and in the hospital overall. 43 percent survived with their native liver, compared to 22 percent of children who did not receive NAC.  And death rates while awaiting transplant, after transplant, and after ten years were notably lower in children who had received NAC. Adverse effects were mentioned in just 11 percent of cases and NAC was discontinued in one.

“Our data demonstrates that NAC has minor, self-limited adverse effects and can be safely administered to children with non-acetaminophen induced acute liver failure,” the authors report. “Additionally this study suggests NAC may have a positive effect on the outcome of non-acetaminophen induced acute liver failure, improving the survival with native liver as well as post liver transplant survival.”

An accompanying editorial by Mike Leonis and William Balistreri of the Cincinnati Children’s Hospital Medical Center points out that the two groups compared in Kortsalioudaki’s study were markedly dissimilar in their clinical presentation which could account for some of the differences in outcomes. Also, further stratification of the NAC-treated group into middle and later years showed better outcomes in the latter group which would argue that the improvement was due to non-NAC related effects.

“This study does support the idea that intravenous NAC is a well-tolerated and safe medication for pediatric patients with acute liver failure,” Leonis and Balistreri write. However, it raises further question as to whether intravenous NAC is beneficial in pediatric patients with non-acetaminophen induced acute liver failure.

They point out that two current randomized-controlled prospective clinical trials are addressing this question. “Hopefully with the completion of both of these studies, convincing information will be available to guide clinicians on the true utility of NAC in non-APAP-induced ALF,” they conclude.

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Article: “Safety and efficacy of N-Acetylcysteine in children with non-acetaminophen induced acute liver failure.” Kortsalioudaki, Christine; Taylor, Rachel; Cheeseman, Paul; Bansal, Sanjay; Mieli-Vergani, Giorgina; Dhawan, Anil. Liver Transplantation; January 2008.

Editorial: “Is there a ‘NAC’ to treating acute liver failure in children.” Leonis, Mike; Balistreri, William. Liver Transplantation; January 2008.

Too much sugar turns off gene that controls the effects of sex steroids

 

 

Eating too much fructose and glucose can turn off the gene that regulates the levels of active testosterone and estrogen in the body, shows a new study in mice and human cell cultures that’s published this month in the Journal of Clinical Investigation. This discovery reinforces public health advice to eat complex carbohydrates and avoid sugar. Table sugar is made of glucose and fructose, while fructose is also commonly used in sweetened beverages, syrups, and low-fat food products. Estimates suggest North Americans consume 33 kg of refined sugar and an additional 20 kg of high fructose corn syrup per person per year.

 

Glucose and fructose are metabolized in the liver. When there’s too much sugar in the

diet, the liver converts it to lipid. Using a mouse model and human liver cell cultures, the

scientists discovered that the increased production of lipid shut down a gene called

SHBG (sex hormone binding globulin), reducing the amount of SHBG protein in the

blood. SHBG protein plays a key role in controlling the amount of testosterone and

estrogen that’s available throughout the body. If there’s less SHBG protein, then more

testosterone and estrogen will be released throughout the body, which is associated with

an increased risk of acne, infertility, polycystic ovaries, and uterine cancer in overweight

women. Abnormal amounts of SHBG also disturb the delicate balance between estrogen

and testosterone, which is associated with the development of cardiovascular disease,

especially in women.

 

“We discovered that low levels of SHBG in a person’s blood means the liver’s metabolic

state is out of whack – because of inappropriate diet or something that’s inherently wrong

with the liver – long before there are any disease symptoms,” says Dr. Geoffrey

Hammond, the study’s principal investigator, scientific director of the Child & Family

Research Institute in Vancouver, Canada, and professor in the Department of Obstetrics

& Gynecology at the University of British Columbia.

* Requested Repost 2007

 

Interferon does not slow or stop hepatitis C from worsening, study finds

 

 

Interferon does not slow or halt the progression of chronic hepatitis C and advanced liver disease in patients who haven’t responded to previous attempts to eradicate the disease, a national study in which the Saint Louis University School of Medicine participated has found.

 

Patients in the trial who were treated with interferon did experience a significant decrease in viral levels and liver inflammation, but the trial unequivocally demonstrated that treatment with long-term pegylated interferon – also called peginterferon – does not prevent the worsening of liver disease in patients who’ve failed prior treatments

 

“The results are this study are very clear – long-term therapy with peginterferon for those with chronic hepatitis C is not effective in preventing progression of liver disease for patients who did not respond to an initial course of treatment,” said Adrian Di Bisceglie, M.D., professor of internal medicine at Saint Louis University School of Medicine and chairman of the trial’s steering committee.

Results of the study were reported by Di Bisceglie at the annual meeting of the American Association for the Study of Liver Disease in Boston this week.

 

The randomized, multi-site study involved 1,050 patients with chronic hepatitis C who’d failed prior treatments to eradicate the infection. All had advanced liver fibrosis – a gradual scarring of the liver that puts patients at risk for progressive liver disease.

 

At the end of the study, while patients treated with interferon did have significantly lower blood levels of the hepatitis C virus and less liver inflammation, 34.1 percent of them had experienced one or more of the following outcomes: excess fluid in the abdomen; brain and nervous system damage; cirrhosis (for those who did not have it initially); liver cancer; or death. Of patients in the control group, 33.8 percent experienced one or more of the outcomes.

* Requested Repost

Researchers surprised to find fatty liver disease poses no excess risk for death

Condition prevalent among those with heart disease and obesity

Non-alcoholic fatty liver disease (NAFLD) is a common condition associated with obesity and heart disease long thought to undermine health and longevity. But a new study by Johns Hopkins researchers suggests the condition does not affect survival.

A report on the study was published online last week in BMJ, the British medical journal.

“Physicians have considered fatty liver disease a really worrisome risk factor for cardiovascular disease,” says study leader Mariana Lazo, M.D., Ph.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine’s Welch Center for Prevention, Epidemiology, and Clinical Research. “Our data analysis shows this doesn’t appear to be the case. We were surprised to say the least because we expected to learn by how much non-alcoholic fatty liver disease increased the risk of death and instead found the answer was not at all.”

Using health information collected from 11,371 Americans between 1994 and 1998 and followed for up to 18 years as part of the Third National Health and Nutrition Examination Survey (NHANES III), the researchers checked liver enzyme levels and ultrasound tests for evidence of NAFLD, and ultimately looked at death rates associated with NAFLD. The participants ranged in age from 20 to 74 during the data collection years. Because the ultrasounds were originally taken to assess gallbladder health, Lazo and colleagues from Johns Hopkins looked at each recording to determine the presence of fat in each person’s liver. People whose livers are 5 percent fat or more are considered to have NAFLD.

The Johns Hopkins team found no increase in mortality among those with NAFLD, which was identified in approximately 20 percent of the NHANES participants. At the end of the follow-up period, mortality from all causes was 22 percent, or 1,836 individuals. Cardiovascular disease was the cause of death for 716 participants, cancer for 480 and liver disease for 44.

Although the researchers found no increase in deaths, Lazo says further study is needed to determine whether more advanced NAFLD has serious long-term consequences for the liver, a vital organ that turns what we eat and drink into nutrients and filters harmful substances from the blood.

NAFLD, which some researchers have called the nation’s next epidemic, is characterized by the liver’s inability to break down fats and fatty build up in the organ.  Found in roughly one in three Americans, it is most prevalent in those who are obese, and those with diabetes and cardiovascular disease. The spectrum of disease ranges from simple fat build-up to inflammation to the scarring and poor liver function that characterize cirrhosis. Chronic liver disease has long been associated with long-term alcohol consumption, but as the name suggests, NAFLD is found in those who are not heavy drinkers.

“We don’t yet know why mortality is not affected or whether there might be some actual protective effect of non-alcoholic fatty liver disease,” she says, “but it looks like the liver’s ability to accumulate fat may somehow shield the body from the detrimental effects of other health problems such as obesity and diabetes,” she says.

There is no treatment for NAFLD, other than lifestyle changes, including weight loss, and only a liver biopsy can determine how serious NAFLD is. Lazo says she hopes new methods are developed that more easily identify more advanced stages of NAFLD, which may not be harmless.

Still, she says, her research suggests that with respect to long-term survival of people with non-alcoholic fatty liver disease, “it may not matter if you have the disease or not.”

###

 

The research was supported by grants from the National Institute of Diabetes and Digestive Diseases and the American Diabetes Association.

Other Johns Hopkins researchers involved in the study include Ruben Hernaez, M.D., Ph.D.; Susanne Bonekamp, Ph.D.; Ihab R. Kamel, M.D., Ph.D.; Frederick L. Brancati, M.D.; Eliseo Guallar, M.D., M.P.H.; and Jeanne M. Clark, M.D., M.P.H.

For more information:http://www.jhsph.edu/welchcenter/