Healthcare Tips

News From The Journal Of Clinical Investigation: July 12, 2010

September 03, 2017

IMMUNOLOGY: Drugs for high blood pressure of benefit in multiple sclerosis?

The hormone angiotensin II (Ang II) is a key regulator of blood pressure. Drugs that block the molecules to which Ang II binds to mediate its effects (AT1Rs) are used to treat high blood pressure. Now, a team of researchers, led by Lawrence Steinman, at Stanford University School of Medicine, Stanford, has identified Ang II as a molecule that sustains inflammation in the brain in mice with a disease that models multiple sclerosis. The effects of Ang II were a result of its ability to promote production of the soluble immune factor TGF-beta in the brain. Importantly, a molecule that blocks AT1Rs reduced the severity of disease in the model of multiple sclerosis by reducing TGF-beta production. The authors therefore suggest that the AT1R-blocking drugs used to treat high blood pressure might be of benefit to individuals with multiple sclerosis.

Title: Angiotensin II sustains brain inflammation in mice via TGF-beta

VACCINE DESIGN: Targeting malaria-causing parasites in the blood

There is currently no vaccine against malaria. The vaccine that is in late-stage clinical trails is designed to target the malaria-causing parasites in the skin and liver, and it reduces the risk of disease by approximately 30-50%. A vaccine that targets the malaria-causing parasite while it is in the blood is likely to provide even more benefit, but such vaccines have been hard to design and develop. However, a team of researchers, led by Michael Good, at the Queensland Institute of Medical Research, Australia, has generated data in mice that suggest that it might now be possible to develop such vaccines. Specifically, they found that administering low doses of killed malaria-causing parasite together with molecules known as CpG-ODN triggered in mice an immune response that targeted malaria-causing parasites in the blood and provided durable and cross-strain protection against disease. The authors hope that their approach might be applicable in humans.

Title: Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice

NEUROBIOLOGY: Protein mislocalization gets nerve cells all excited

Individuals with the childhood epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+) suffer generalized epilepsies of variable severity and febrile seizures, which are convulsions brought on by a fever. GEFS+ is often associated with genetic mutations that alter the function of proteins known as sodium channels. To investigate how such mutations cause the symptoms of GEFS+, a team of researchers, led by Steven Petrou, at The University of Melbourne, Australia, generated mice expressing one copy of a mutated gene associated with GEFS+ in humans. This gene made a C121W mutant version of the beta-1 sodium channel accessory subunit protein. Detailed analysis of the mice led the team to conclude that the beta-1 sodium channel accessory subunit protein normally modulates the excitability of regions of pyramidal nerve cells known as the axon initial segments and that the C121W mutant protein was excluded from such regions, thereby disrupting the regulation of axon initial segment excitability and causing epilepsy.

Title: Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

ONCOLOGY: Pathways to cancer: follow the protein Gankyrin

Mutations that activate Ras proteins drive cancer onset and progression and are found in approximately 30% of human cancers. Despite their key role in human disease, the tumorigenic pathways downstream of activated Ras have yet to be completely defined. Data generated by Xue-Min Zhang, Hui-Yan Li, and colleagues, at the National Center of Biomedical Analysis, China, has identified a new molecular pathway with an essential role in Ras-initiated tumorigenesis in mouse and human cells.

Specifically, Zhang, Li, and colleagues found that the protein Gankyrin increases interaction between two proteins known as RhoA and RhoGDI; this decreases RhoA activity, which leads to inhibition of the protein ROCK; this in turn prolongs activation of the protein Akt, an event known to be critical in activated Ras-induced tumor onset and progression. As the authors find that Gankyrin is a critical mediator of Ras-induced tumorigenesis, they suggest it could be a therapeutic target for the treatment of cancers caused by activating Ras mutations.

Title: Gankyrin plays an essential role in Ras-induced tumorigenesis through regulation of the RhoA/ROCK pathway in mammalian cells

BONE BIOLOGY: Generation of bone-destroying cells promoted by the protein ATF4

Maintaining healthy bone density requires that the number of bone-forming cells (osteoblasts) is balanced by the number of bone-destroying cells (osteoclasts). Increased numbers and/or function of osteoclasts is a feature of diseases such as osteoporosis, Paget disease of bone, and rheumatoid arthritis. A team of researchers, led by Guozhi Xiao, at the University of Pittsburgh, Pittsburgh, has now generated several lines of evidence that indicate that the gene regulatory protein ATF4 has an important role in promoting the generation of osteoclasts in mice. For example, the generation of osteoclasts in ATF4-deficient bones was dramatically reduced when compared with the generation of such cells in normal bones. The authors therefore suggest that targeting ATF4 might provide a way to treat diseases associated with increased osteoclast numbers and/or activity.

Title: Activating transcription factor 4 regulates osteoclast differentiation in mice

HEPATOLOGY: Integrating death-inducing and survival signals in liver disease

Acute (fulminant) hepatitis is a major cause of drug-induced liver failure. The protein Fas plays a role in the establishment of fulminant hepatitis because its activation elicits signals to surrounding cells that induce their death and others that protect them. The mechanisms by which these signals are integrated during disease are unknown. Insight into this has now been provided by a team of researchers, led by Rama Khokha, at the Ontario Cancer Institute, Toronto, through their analysis of several strains of genetically engineered mice. Specifically, the team found that the proteins TIMP3 and ADAM17 cooperate to integrate the survival and death-inducing signals triggered by Fas activition during the acute liver stresses that can lead to fulminant hepatitis.

Title: Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

Karen Honey
Journal of Clinical Investigation