Chronic HgCl2 treatment increases vasoconstriction induced by electrical field stimulation. Role of adrenergic and nitrergic innervation

Clinical Science (2011) Immediate Publication, doi:10.1042/CS20110072 Chronic HgCl2 treatment increases vasoconstriction induced by electrical field stimulation. Role of adrenergic and nitrergic innervationJavier Blanco-Rivero, Lorena B Furieri, Dalton V Vassallo, Mercedes Salaíces and Gloria BalfagónFisiología, Facultad de Medicina. Universidad Autónoma de Madrid, Madrid, Madrid 28029, Spain. gloria.balfagon@uam.es

Objectives: We investigated the possible changes in rat mesenteric artery vascular innervation function caused by chronic exposure to low doses of mercuric chloride (HgCl2), as well as the mechanisms involved.

Methods: Rats were divided into two groups: control and HgCl2-treated rats (30 days, 1st dose 4.6 µg/kg, subsequent dose 0.07 µg/kg·day im). Vasomotor response to electrical field stimulation (EFS), noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied, neuronal NO synthase (nNOS) and phosphorylated nNOS (P-nNOS) protein expression were analysed and NO, superoxide anions (O2.-) and NA releases were also determined.

Results: EFS-induced contraction was higher in the HgCl2-treated group. 1 mmol/L phentolamine decreased the response to EFS to a greater extent in HgCl2-treated rats. HgCl2 treatment increased vasoconstrictor response to exogenous NA and NA release. 0.1 mmol/L L-NAME increased the response to EFS in both experimental groups but the increase was greater in segments from control animals. HgCl2 treatment decreased NO release and increased O2.- production. Vasodilator response to DEA-NO was lower in HgCl2 animals. Tempol increased DEA-NO-induced relaxation to a greater extent in HgCl2-treated animals. nNOS expression was similar in arteries from both experimental groups, while P-nNOS was decreased in segments from HgCl2-treated animals.

Conclusion: HgCl2 treatment increased vasoconstrictor response to EFS as a result, at the least, of reduced NO bioavailability and increased adrenergic function. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

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Autologous Induced Pluripotent Stem Cells And Gene Repair Therapy For Treatment Of Familial Hypercholesterolemia

Study shows, for the first time, the successful reprogramming of diseased human hepatocytes into induced pluripotent stem cells (iPSC).1

Results also found differentiation into mature hepatocytes was more efficient than that with fibroblast-derived iPSCs.

The generation of diseased hepatocyte-derived human iPSC lines provides a good basis for the study of liver disease pathogenesis.

Such technology could give a potentially unlimited reservoir of cells for the treatment of human liver diseases: generating genetically corrected liver cells via auto-transplantation of genetically modified hepatocytes, thus avoiding liver transplant and lifelong immunosuppression.

References:
1 Bosman, A. et al. Progress toward the clinical application of autologus induced pluripotent stem cells and gene repair therapy for treatment of familial hypercholesterolemia. Abstract presented at The International Liver CongressTM 2011.

Source:
Travis Taylor
European Association for the Study of the Liver

Pig Stem Cell Transplants: The Key To Future Research Into Retina Treatment

A team of American and Chinese scientists studying the role of stem cells in repairing damaged retina tissue have found that pigs represent an effective proxy species to research treatments for humans. The study, published in Stem Cells, demonstrates how cells can be isolated and transplanted between pigs, overcoming a key barrier to the research.

Treatments to repair the human retina following degenerative diseases remain a challenge for medical science. Unlike species of lower vertebrates the human retina lacks a regenerative pathway meaning that research has focused on cell transplantation.

"The retina is the light sensitive tissue surrounding the inner surface of the eye. Its outer layer is made up of rods and cone photoreceptor cells which convert light signals," said lead author Douglas Dean from the University of Louisville. "Traditionally transplant studies have focused on mice and other rodents because of the variety of genetic material they represent, however mouse retina tissue is rod dominant, which is significantly different to the human eye."

Dr Dean's team turned their attention to pigs because, as with humans, the swine eye contains a cone dominant central visual streak, making it a closer anatomical and physiological match.

"Studies into swine models have been hampered in the past," said Dean, "because the induced pluripotent stem cells (iPSCs) needed for such transplants have not been isolated from pigs, while their compatibility with a host's photoreceptor cells had not been demonstrated."

Dr Dean's team gathered iPSCs from swine skin fibroblasts and demonstrated that these cells differentiated in culture and could be integrated with the cells of a second pig's retina.

While only a small section of the retina was transplanted for this study the results could open a new avenue of research into degenerative conditions as researchers have a more effective human proxy species to work with.

"Our results demonstrate that swine stem cells can be integrated into a damaged swine neural retina," concluded Dean. "This research now lays a foundation for future studies of retinal stem cell transplantation in a swine model."

Full citation: Zhou. L, Wang. W, Liu. Y, Fernandez de Castro. J, Ezashi. T, Telugu. B, Roberts. M, Kaplan. H, Dean. D, "Differentiation of Swine iPSC into Rod Photoreceptors and Their Integration into the Retina", Stem Cells, Wiley-Blackwell, DOI: 10.1002/stem.637

Source:
Alpha Med Press
Wiley-Blackwell

 

Cardiac Stem Cell Treatment For Heart Failure Discussed By Roberto Bolli At Cannon Lecture

Heart failure affects roughly six million Americans, yet treatment consists of either a heart transplant or the insertion of mechanical devices that assist the heart. This is unacceptable to Roberto Bolli, MD, Chief of the Division of Cardiovascular Medicine at the University of Louisville in Louisville, Ky., which is why he is on a mission to make cardiac stem cell treatment an option for all who must cope with the limitations of a failing heart.

Dr. Bolli is conducting the groundbreaking study, "Cardiac Stem Cell Infusion in Patients with Ischemic cardiOmyopathy (SCIPIO)," in which researchers at the University of Louisville's Jewish Hospital are collaborating with a team led by Piero Anversa, MD, at the Brigham and Women's Hospital in Boston to perfect a technique for using a patient's own cardiac stem cells to regenerate dead heart muscle after a heart attack.

In honor of his illuminating work, the American Physiological Society (APS) selected Dr. Bolli to present the Walter B. Cannon Memorial Lecture at the Experimental Biology 2011 meeting (EB 2011). This lecture is the Society's pre-eminent award lecture and is designed to recognize an outstanding scientist for his or her contributions to the field.

A Tale of Two Proteins

The cardiac stem cell treatment investigated in the SCIPIO trial consists of isolating the patient's cardiac stem cells from part of the upper chamber of the heart (harvested during coronary bypass surgery) and expanding these cells in the lab. Four months after surgery, the cells are infused into scarred cardiac tissue by catheterizing a large artery in the patient's leg. Using the patient's own cardiac stem cells eliminates the possibility of rejection.

Besides SCIPIO, Dr. Bolli is also performing basic research aimed at on enhancing the cardiac stem cells while they are cultured in the lab for expansion. He is working with two proteins, heme oxygenase 1 (HO-1) and nitric oxide synthase (NOS). HO-1 is a protein made in response to cellular stress, such as oxidative stress or oxygen deficiency. It catalyzes the breakdown of heme, which is a molecular component of hemoglobin, the part of the red blood cell that transports oxygen around the body. When HO-1 breaks down heme, one of the by-products is carbon monoxide (CO). NOS, the other protein Dr. Bolli is investigating, is an enzyme that catalyzes the production of nitric oxide (NO). Dr. Bolli is focusing on these two proteins because their catalytic by-products, CO and NO, exert remarkable beneficial effects.

"When the heart muscle is dying because of a heart attack, these gases (CO and NO) are extremely cardioprotective and help the tissue survive," he says. "We are now applying these same proteins to stem cells, using the knowledge that we have gained from 20 years of research in cardioprotection."

A Promising Future

So far, the results are promising. "We have exciting data indicating that if we increase these proteins in stem cells, the stem cells become more resilient and more effective at repairing damage," Dr. Bolli says.

Even with natural cells (in which these proteins are not increased), such as those used in SCIPIO, the results are very encouraging. Improvements seen in patients who have received cardiac stem cell infusion include increased ejection fraction, the fraction of blood pumped through the two lower chambers of the heart. Patients also experience dramatic improvements in what they are able do physically, Dr. Bolli says. "There are people who are almost completely incapacitated, and after they get stem cells, they can do so much more. I have a patient who couldn't walk to the bathroom, and now he can walk two miles."

Dr. Bolli cautions that SCIPIO is a Phase 1 trial, meaning that it is the first round of testing in humans. Its primary purpose is to assess safety and feasibility, rather than efficacy. Yet, he remains optimistic and notes that cardiac stem cells offer the hope of healing the heart. "All of the other treatments currently available - transplants, assist devices, drugs - may prolong life but do not solve the problem. By regenerating new heart muscle, cardiac stem cells could actually solve the problem."

To date, 17 patients have received cardiac stem cells in the SCIPIO trial. Dr. Bolli discussed his research and provided the latest details of how the patients are faring when he presented this year's Cannon Lecture, "The nitric oxide-carbon monoxide module: A fundamental mechanism of cellular resistance to stress," on Saturday, April 9 at the Walter E. Washington Convention Center.

Walter B. Cannon Award Lecture

The Cannon Award lectureship, established in 1982, is the APS' highest award. The individual selected is an outstanding physiological scientist chosen by the President-Elect, with the consent of Council, to lecture on "Physiology in Perspective" during the plenary session of the Society's next annual meeting. At the 1984 fall meeting, the title of the presentation was changed to "Physiology in Perspective: The Walter B. Cannon Lecture."

Source:
Donna Krupa
American Physiological Society

 

Potential Treatment For Chemotherapy-Resistant Chronic Myeloid Leukaemia

Speaking at the UK National Stem Cell Network conference in York later today (31 March), Professor Tessa Holyoake from the University of Glasgow will discuss a brand new approach to treating chronic myeloid leukaemia (CML) in which a small number of cancer cells persist despite effective therapy thus preventing cure.

CML is a type of blood cancer caused by the infamous "Philadelphia Chromosome" genetic abnormality. It is usually treated using a class of drugs called Tyrosine Kinase Inhibitors and in the majority of cases this treatment is successful, with around 90% of patients recovering from the disease. However in the majority of patients a subset of cancer cells - CML stem cells - are resistant to Tyrosine Kinase Inhibitors.

"At the moment we are working with 9 patients who still have low level evidence of CML despite Tyrosine Kinase Inhibitor treatment. They are helping us to test the use, in principle, of a new type of drug that specifically deals with the resistant CML stem cells," said Professor Holyoake.

"The drug we are using in the trial is hydroxychloroquine - a well established antimalarial drug that has been used commonly since the 1950s and is also used in rheumatoid arthritis. This will allow us to test the principle of using similar drugs to treat CML patients.

"Unfortunately hydroxychloroquine may not be suitable for very long term treatment because of side effects. In particular there is a very low risk of temporary or permanent eye problems. In our trial the patients will take the drug for up to 12 months with very close monitoring of their eye health, which will allow us to intervene at the very earliest sign of an adverse effect," Professor Holyoake continued.

The patients in the trial have already taken a Tyrosine Kinase Inhibitor drug for at least a year, which has reduced the number of cancer cells in their blood to a very low level.

Professor Holyoake's team discovered that CML stem cells avoid the impact of Tyrosine Kinase Inhibitor treatments by going into a state called autophagy in response to the drug. This means that they begin to shut down and use nutrients from within the cell to survive in what is effectively suspended animation. In this state the drug cannot kill them and so later they can initiate a resurgence of the disease. Hydroxychloroquine has been shown to kill cells that are undergoing autophagy and the trial is designed to test whether this is a potential route for treatment in patients.

Professor Holyoake concluded "Although hydroxychloroquine probably isn't the final answer for treating resistant CML stem cells, we are aware that there is interest from the pharmaceuticals industry in developing new drugs that target cells undergoing autophagy. We are therefore very hopeful that once we can prove that in principle this approach works, it could lead relatively quickly to a new treatment for patients for whom Tyrosine Kinase Inhibitors don't provide a full cure."

Source:
Mike Davies
Biotechnology and Biological Sciences Research Council

 

NICE Recommends New Treatment For Myelodysplastic Syndromes

NICE has today issued final guidance recommending azacitidine (Vidaza, Celgene) as a treatment option for people with myelodysplastic syndromes (MDS).

Azacitidine has been recommended in line with its licensed indications, which means that it is now a treatment option for patients that have one of the following conditions and who are not eligible for haematopoietic stem cell transplantation: intermediate-2 and high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia.

Dr Carole Longson, Health Technology Evaluation Centre Director at NICE said: "We are pleased to be able to recommend this new treatment for MDS - it is not a cure, but it has the potential to extend life expectancy for these patients. During consultation on the draft recommendations, the manufacture of azacitidine offered to provide the drug at a reduced price. Azacitidine is an expensive drug, and this discount enabled us to recommend it as a cost effective use of resources on the NHS."

Myelodysplastic syndromes (MDS) are a group of bone marrow disorders, where the marrow doesn't produce enough of one or more types of blood cells. The majority of patients with MDS receive best supportive care in current clinical practice, and some patients receive low-dose or standard-dose chemotherapy. There are approximately 700 patients in England and Wales with the type of MDS for which azacitidine is licensed.

Notes

About the appraisal

1. The guidance will be available from 23 March here.

2. Azacitidine is the first drug that has been developed specifically for treating myelodysplastic syndromes. It is not a cure, but it does have the potential to extend patients' lives. The clinical trial reported an average life extension of nine months.

3. The Committee agreed that azacitidine met the criteria for being a life-extending, end-of-life treatment and considered that, on balance, the additional weight that would need to be assigned to the QALY benefits in this patient group for the cost effectiveness of azacitidine to fall within the current threshold range was acceptable.

4. The committee agreed that the most plausible ICER for azacitidine in the overall patient population was approximately £47,200 per QALY gained. This included the patient access scheme.

5. The Department of Health and the manufacturer have agreed that azacitidine will be available to the NHS with a patient access scheme in which a discount is applied to all invoices. The level of the discount is confidential. It is the responsibility of the manufacturer to communicate the level of discount to the relevant NHS organisations.

Source:
NICE

 

Autologous Induced Pluripotent Stem Cells And Gene Repair Therapy For Treatment Of Familial Hypercholesterolemia

Study shows, for the first time, the successful reprogramming of diseased human hepatocytes into induced pluripotent stem cells (iPSC).1

Results also found differentiation into mature hepatocytes was more efficient than that with fibroblast-derived iPSCs.

The generation of diseased hepatocyte-derived human iPSC lines provides a good basis for the study of liver disease pathogenesis.

Such technology could give a potentially unlimited reservoir of cells for the treatment of human liver diseases: generating genetically corrected liver cells via auto-transplantation of genetically modified hepatocytes, thus avoiding liver transplant and lifelong immunosuppression.

References:
1 Bosman, A. et al. Progress toward the clinical application of autologus induced pluripotent stem cells and gene repair therapy for treatment of familial hypercholesterolemia. Abstract presented at The International Liver CongressTM 2011.

Source:
Travis Taylor
European Association for the Study of the Liver