Senescent “zombie” cells are linked to aging and multiple diseases, but spotting them in living tissue has been notoriously difficult. Researchers at Mayo Clinic have now taken an inventive leap by using aptamers—tiny, shape-shifting DNA molecules—to selectively tag these elusive cells. The project began as an offbeat conversation between two graduate students and quickly evolved into a collaborative, cross-lab effort that uncovered aptamers capable of binding to unique surface proteins on senescent cells.
Here, Pengda Liu & team show SPOP inhibitors act as molecular glue degraders, stabilizing and activating STING to enhance immunotherapy in melanoma mouse models:
The figure shows the SPOP inhibitor 6lc reduces CBX4 and BMI1 foci, while ectopic CBX4 restores BMI1 foci and H2AX interactions.
4Department of Pharmacology.
5Division of Oncology, Department of Medicine, and.
6UNC Metabolomics and Proteomics Core, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
“I just can’t make it tonight. You have fun without me.” Across much of the animal kingdom, when infection strikes, social contact shuts down. A new study details how the immune and central nervous systems implement this sickness behavior.
It makes perfect sense that when we’re battling an infection, we lose our desire to be around others. That protects them from getting sick and lets us get much needed rest. What hasn’t been as clear is how this behavior change happens.
In the research published in Cell, scientists used multiple methods to demonstrate causally that when the immune system cytokine interleukin-1 beta (IL-1β) reaches the IL-1 receptor 1 (IL-1R1) on neurons in a brain region called the dorsal raphe nucleus, that activates connections with the intermediate lateral septum to shut down social behavior.
“Our findings show that social isolation following immune challenge is self-imposed and driven by an active neural process, rather than a secondary consequence of physiological symptoms of sickness, such as lethargy,” said study co-senior author.
Mayo Clinic researchers have uncovered how aging “zombie cells” trigger harmful inflammation that accelerates a severe and increasingly common form of fatty liver disease called metabolic dysfunction-associated steatohepatitis (MASH). As obesity rates rise worldwide, MASH is projected to increase and is already one of the leading causes of liver transplantation.
“Liver scarring and inflammation are hallmarks of MASH. If left untreated, it can progress to liver cancer. This is why it’s so important to understand the mechanisms driving the disease so that we can prevent it or develop more effective treatments,” says Stella Victorelli, Ph.D., who is the lead author of the study published in Nature Communications.
Dr. Victorelli and colleagues, who study aged or senescent “zombie” cells, identified a mechanism by which these cells drive liver scarring and inflammation. They found that small molecules called mitochondrial RNA, typically found within the cell’s energy-producing mitochondria, can leak into the main part of the cell, where they mistakenly activate antiviral sensors called RIG-I and MDA5—normally triggered when a virus infects a cell. In this case, the danger signal comes from the cell’s own mitochondria, prompting a wave of inflammation that can damage nearby healthy tissue.
Research by University of Sydney scientists has uncovered a mechanism that may explain why glioblastoma returns after treatment, offering new clues for future therapies which they will now investigate as part of an Australian industry collaboration.
Glioblastoma is one of the deadliest brain cancers, with a median survival rate of just 15 months. Despite surgery and chemotherapy, more than 1,250 clinical trials over the past 20 years have struggled to improve survival rates.
Published in Nature Communications, the study shows that a small population of drug-tolerant cells known as “persister cells” rewires its metabolism to survive chemotherapy, using an unexpected ally as an invisibility cloak: a fertility gene called PRDM9.
This issue’s cover features work by Alberto Siddu & team on the promotion of synapse formation in human neurons by free amyloid-beta peptides, in contrast to aggregated forms that are synaptotoxic:
The image shows a human induced neuron exposed to a nontoxic concentration of amyloid-beta42 peptide, revealing enhanced synaptogenesis, visible as synaptic puncta along the dendritic arbor.
Address correspondence to: Alberto Siddu, Lorry Lokey Stem Cell Building, 265 Campus Dr., Room G1015, Stanford, California 94,305, USA. Phone: 650.721.1418; Email: [email protected]. Or to: Thomas C. Südhof, Lorry Lokey Stem Cell Building, 265 Campus Dr., Room G1021, Stanford, California 94,305, USA. Phone: 650.721.1418; Email: [email protected].
Using a new strategy for quantifying mitochondrial DNA, Mark L. Hepokoski & team show the release of mtDNA from the kidney directly contributes to interleukin-6 release during sepsis associated AKI.
1VA San Diego Healthcare System, San Diego, California, USA.
2Division of Pulmonary and Critical Care and Sleep Medicine, UCSD, La Jolla, California, USA.
3Department of Critical Care Medicine, Yantai Yuhuangding Hospital, Affiliated with Medical College of Qingdao University, Yantai, Shandong, China.
It’s well known that exercise is good for health and helps to prevent serious diseases, like cancer and heart disease, along with simply making people feel better overall. However, the molecular mechanisms responsible for preventing cancer or slowing its progression are not well understood. But, a new study, published in the Proceedings of the National Academy of Sciences, reveals how exercise can increase glucose and oxygen uptake in the skeletal and cardiac muscles, instead of allowing it to “feed” tumors.
Reduced tumor growth in exercised mice To study how exercise-induced metabolic changes affect tumor growth, the research team injected mice with breast cancer cells and fed some of the mice a high-fat diet (HFD), consisting of 60% calories from fat, while others were fed a normal diet as a control. The HFD mice were given running wheels for exercise, although exercise was voluntary. The team used stable isotope tracer studies [U-13C6] glucose and [U-13C5] glutamine to track metabolic changes.
After 4 weeks of wheel running, the team found a significant difference in tumor sizes between mice that chose to exercise, compared to those that did not—even when they were fed the same diet.