Lab Notes: Prostate Cancer Takes Nerve
Innervation of prostate tumors appears to be related to their aggressiveness, and may prove to be a viable treatment target. Also this week: unhealthy gut flora go with HIV infection.
Prostate Cancer Takes Nerve
Sympathetic and parasympathetic nerves appear to boost development and spread of prostate tumors, researchers reported in Science
.
In a mouse model, disabling sympathetic nerves controlling the "fight or flight" reflex cut down on the early stages of tumor growth in the prostate. The parasympathetic nerve fibers infiltrating the tumor were linked to dissemination of cancer cells.
"Our findings raise the tantalizing possibility that drugs targeting both branches of the autonomic nervous system may be useful therapies for prostate cancer," lead author Paul Frenette, MD, of Albert Einstein College of Medicine in New York City, suggested in a statement.
Analysis of human prostate tissue specimens taken before treatment indicated a higher density of nerve fibers in and around tumors that turned out to be aggressive.
"More work needs to be done, but the findings suggest that nerve density assessment merits further study as a possible predictive marker of prostate cancer aggressiveness," Frenette added.
-- Crystal Phend
Bad Bugs Abet HIV
Increasingly, the ill effects of HIV infection -- even when controlled by highly active antiretroviral therapy (HAART) -- are being linked to chronic inflammation. Now researchers led by Joseph McCune, MD, PhD, of the University of California San Francisco, think they understand at least part of the reason.
They analyzed the gut microbiome -- all the bacteria that live in the intestinal tract -- of 34 people, including seven with untreated HIV, 18 with HIV controlled by HAART, and nine without HIV but matched for other health risks. The HIV patients, according to a report online in Science Translational Medicine
, had a markedly different gut microbiome than did the uninfected participants.
Specifically, they harbored more harmful species, such as Pseudomonas
, Salmonella, Escherichia coli, and Staphylococcus, that can cause inflammation. The extent of the so-called dysbiosis was correlated with tryptophan catabolism and plasma concentrations of the inflammatory cytokine interleukin-6, which are known markers of HIV progression.
One implication, they concluded, is that intestinal microbiomic engineering in HIV patients might be a new therapeutic strategy for managing disease progression.
-- Michael Smith
Mechanism Found for Novel Acute Kidney Injury Drug
Researchers have discovered how a drug currently being investigated in phase II trials for heart and kidney disease protects against acute kidney injury.
Acute kidney injury is most often caused by ischemia, which damages the mitochondria and limits their ability to produce ATP. Hazel Szeto, MD, PhD, of Weill Cornell Medical College, and colleagues recently reported that a drug called SS-31 -- or Bendavia -- improved ATP recovery after ischemia and reduced acute kidney injury in rats, although the mechanism had been unknown.
In a new study reported in the Journal of the American Society of Nephrology
, the researchers found that the drug binds to a phospholipid called cardiolipin, located on the inner mitochondrial membrane and a key component of ATP production. The drug-cardiolipin complex helped prevent some of the damage that occurred during ischemia.
Pretreating rats with the drug protected mitochondrial membranes, prevented mitochondrial swelling during renal ischemia and allowed rapid recovery of ATP on reperfusion.
"Our results show that SS-31 is very effective in preventing acute ischemia-reperfusion injury and suggest that it may be beneficial for conditions where renal ischemia is predictable, such as sepsis, shock, and cardiovascular surgery," Szeto and colleagues wrote.
-- Todd Neale
Folate Good for Baby
Before and After Pregnancy
Folate supplementation during pregnancy and for babies after birth might offer previously unrecognized metabolic benefits for children, according to a study involving laboratory rats.
Male pups of rats fed a high-folate diet during pregnancy and then weaned to recommended multivitamin levels had the highest food intake and highest body weight at the end of 29 weeks, consistent with previous observations of obesity and metabolic syndrome associated with gestational multivitamin supplementation.
In contrast, folate supplementation during pregnancy and in pup chow led to significantly less food intake (P
=0.02), lower body weight (P=0.03), reduced glucose response to a glucose load (P=0.02), and to improved glucose response to insulin (P=0.009).
"High folate alone in either gestational or pup diet modified gene expression of feeding related neuropeptides," G. Harvey Anderson, MD, of the University of Toronto, and co-authors concluded in an article published online in Epigenetics
.
Continuation of folate in pup chow was associated with hypomethylation of a promoter involved in regulation of glucose response. The results show that the "obesogenic phenotype of offspring from dams fed the high-folate gestational diet can be corrected by feeding them a high-folate diet."
-- Charles Bankhead
Gamma-Secretase Still a Popular Alzheimer Target
The failure of several inhibitors of gamma-secretase -- one of the enzymes responsible for cleaving beta-amyloid protein from a larger precursor molecule -- to slow progression of Alzheimer's disease clinical trials has not persuaded researchers to give up on it as a treatment target.
At a press briefing held at Alzheimer's Association International Conference in Boston, a group from Brigham and Women's Hospital (also in Boston) described efforts to develop new and improved gamma-secretase inhibitors, which, they said, appear to outperform avagacestat. The latter was the most recent beta-amyloid inhibitor to crash and burn in a clinical trial, leading its sponsor to cancel development.
Led by Corinne Augelli-Szafran, PhD, the Brigham & Women's group reported on their iterative design program that had produced several potential candidates with in vitro activity indicating potent gamma-secretase inhibition and reductions in beta-amyloid protein release, along with Notch selectivity and other desirable characteristics such as blood-brain barrier penetration.
Three of these compounds, when tested in mice, significantly lowered beta-amyloid in the brain. Additional compounds developed subsequently showed even better potency and selectivity, the researchers said. -- John Gever
