Drug Might Help Treat Sepsis
News May 18, 2016
Sepsis is a life-threatening condition in which the body launches a massive immune response to an infection. It can be triggered by different types of microbes (such as viruses and bacteria). To combat infections, the body turns on antimicrobial genes that cause the production and release of inflammatory chemicals into the affected site and bloodstream. This response is essential for the body’s protection, but its over-activation can cause widespread and exaggerated inflammation that can result in tissue damage, organ failure, and sometimes death.
A team of scientists led by Dr. Ivan Marazzi at the Icahn School of Medicine at Mount Sinai investigated antimicrobial gene activation during infection to better understand the body’s immune response to microbes. The research was funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results appeared online on April 28, 2016, in Science.
The researchers exposed mouse and human cells infected with flu viruses to various chemicals that block gene activation. By looking at the expression of genes known to be turned on during viral infection, they observed that one chemical, camptothecin (CPT), reduced virus-induced gene activation. CPT blocks a DNA enzyme called topoisomerase 1 (Top1). Genetic depletion of Top1 in flu virus-infected cells reduced the expression of 84 genes—predominantly genes that are specifically induced in response to infection.
Another drug that's similar to CPT and also blocks Top1, topotecan (TPT), prevented the activation of antimicrobial genes in human cells infected with either bacteria or Ebola virus. The researchers mapped the genomic distribution of TPT and found that TPT sits near regions of DNA that turn on antimicrobial genes, called promoters. Top1 is reduced at such sites when TPT is present.
The scientists administered CPT to mice with severe inflammatory responses. They found that 70% to 94% of mice treated with the drug were rescued from a lethal reaction caused by either infection with the bacteria Staphylococcus aureus, co-infection with both a flu virus and Staphylococcus aureus, or acute liver failure. Together, the results suggest that drugs that inhibit Top1 may help control dangerous inflammatory responses.
“Our findings suggest a therapeutic usage of Top 1 inhibition for the treatment of severe-and sometimes lethal inflammatory conditions in people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes—what is known as a cytokine, or inflammatory, storm,” says Marazzi.
Drugs that are similar to CPT, such as TPT, are already FDA-approved as anticancer agents. More studies are needed to test whether they would be useful for treating sepsis.
Cryo-EM Reveals Interaction Between Major Drug TargetsNews
For the first time, scientists have visualized the interaction between two critical components of the body's vast cellular communication network, a discovery that could lead to more effective medications with fewer side effects for conditions ranging from migraine to cancer.READ MORE
New Ovarian Cancer TargetNews
Researchers have found a prescription drug, Calcitriol, approved by the Food and Drug Administration for the treatment of calcium deficiency and kidney diseases, may increase the likelihood of surviving ovarian cancer. This new study opens a potential avenue for treating ovarian cancer. Since Calcitriol is an FDA-approved drug, no additional research is needed before the drug can advance to human clinical trials for ovarian cancer.READ MORE
Novel Microplate 3D Bioprinting Platform for Engineering Muscle and Tendon TissuesNews
There is a strong need for medication that treats age-related degenerative muscle and tendon diseases. A critical bottleneck in the discovery and development of novel drugs for skeletal muscle is the lack of efficient and robust functional in vitro assays for compound screening. Researchers describe the development of a novel screening platform with automated production of 3D muscle- and tendon–like tissues using 3D bioprinting.READ MORE