Another Bite at Leptin

Scientists at the South Korean University of Ulsan Medical Center discovered a protein in the brain that is important for regulating feeding and appetite. The protein works through its effects on the receptor for leptin, a critical weight-regulating hormone that is secreted by fat cells and signals to the hypothalamus, the area of the brain most critical for feeding and appetite. Clusterin works in concert with the protein LRP2, a leptin co-receptor. Obese individuals typically are resistant to leptin, but the authors found that administering clusterin to obese mice led to weight loss even when the animals already were resistant to leptin. The authors concluded that "emergence of clusterin and LRP2 as novel appetite regulators could lead to new therapeutic options for obese individuals with leptin resistance," although they also noted that weight loss of mice treated with clusterin was only modest over time, which might mean that similar resistance can develop as to leptin itself. The work appeared in the May 14, 2013, issue of Nature Communications.

Getting at KRAS via PDE-delta

Researchers from the German Max Planck Institute for Molecular Physiology have come up with an indirect way to inhibit KRAS, a protein that is often mutated in cancer but has so far foiled any attempts to target it directly. Activated KRAS moves through the cytoplasm to jump-start growth signaling pathways, and one of the proteins that helps it do so is PDE-delta. The authors found that when they inhibited the interaction of KRAS and PDE delta by targeting PDE delta, they were able to slow the growth of pancreatic cancer cells both in cell cultures and in xenografted animals. The findings suggested a new approach to targeting KRAS, which can acquire driver mutations in lung and colorectal cancers as well as pancreatic cancers and controls signaling of other proteins that are themselves often mutated in cancer, such as PI3 kinase. The study appeared in the May 23, 2013, issue of Nature.

Bacteriophages: An External Immune System?

Researchers from San Diego State University have discovered that phages, or viruses that are specialized on infecting bacteria, may provide immune protection to higher organisms, including humans. The authors found high concentrations of phages on mucosal surfaces, which are the main points of entry for bacteria into their hosts. Genomic analyses suggested that phages and mucosal surfaces co-evolved to enable the former to bind to the latter. "This benefits the . . . host," the authors explained, "by limiting mucosal bacteria, and benefits the phage through more frequent interactions with bacterial hosts." The findings described an external immune system of sorts, which has some parallels to the beneficial bacteria that are now recognized as being vital to human health. "This has far-reaching implications for numerous fields, such as human immunity, gastroenterology, coral disease, and phage therapy." The work appeared in the May 20, 2013, advance online issue of the Proceedings of the National Academy of Sciences.

Grapefruit Fat for Drug Delivery

Grapefruit juice is best known for interfering with drug delivery, since it interacts with enzymes that metabolize many drugs. But scientists from the University of Louisville have developed nanoparticles from grapefruit lipids that may be useful as drug delivery vehicles. The authors named those vehicles grapefruit-derived nanovectors, and such nanovectors could be targeted to cells expressing folate receptors – a category that includes some tumor cells – by administering them together with folic acid. The authors were able to deliver both siRNAs and small-molecule drugs with their vectors. Chemotherapy-containing nanovectors slowed tumor growth in xenografted mice. The authors noted that their grapefruit-derived nanovectors "are less toxic than nanoparticles made of synthetic lipids and, when injected intravenously into pregnant mice, do not pass the placental barrier, suggesting that they may be a useful tool for drug delivery." Their work appeared in the May 21, 2013, advance online edition of Nature Communications.

Antibiotic Causes Resistance to Innate Immunity

Scientists at Emory University have discovered that as bacteria developed resistance to the last-line antibiotic colistin, they also developed resistance to innate immune mechanisms. Colistin uses its positive charges to attack bacterial cells walls, which are negatively charged. The authors looked at Acinetobacter baumannii, which causes infections in intensive care units and is resistant to many antibiotics, and found that resistance to colistin correlated with resistance to two antimicrobial proteins that are produced by the innate immune system and also target negatively charged bacterial cell walls. Such resistance raises the specter of hypervirulent strains resistant to the innate immune system in addition to all antibiotics. The authors said they believe their findings are likely typical of the response of bacteria treated with colistin. They urged that "the potential for the induction of cross-resistance to innate immune antimicrobials should be considered during the development of new therapeutics." Their findings appeared in the May 21, 2013, online edition of mBio.

Bone Affects Joints in Osteoarthritis

Researchers from Johns Hopkins University have shown that processes in bone contribute significantly to osteoarthritis, whose main feature is the degeneration of cartilage. They found that in an animal model of injury-induced osteoarthritis, changes to the cartilage after the initial injury quickly led to changes in the ratio of bone-forming osteoblasts and bone-destroying osteoclasts near the site of injury. Ultimately, that led to bone buildup, which further exacerbated the strain on the cartilage. Bone buildup depended on TGF-beta signaling, and the disease was more severe when bone stem cells expressed high levels of TGF-beta, while blocking the action of TGF-beta halted bone disease. The authors concluded that "careful titration of TGF-β activity inhibition may be a possible avenue for the prevention of osteoarthritis or the treatment of its early stages." Their work appeared in the May 19, 2013, issue of Nature Medicine.

Protein Synthesis Imbalance Is Longevity Signal

A team at the Swiss Ecole Polytechnique Federale de Lausanne discovered that a mutation in a mitochondrial ribosomal protein that decreases protein synthesis in mitochondria correlated with an increased lifespan. Furthermore, treating young roundworms with antibiotics that block that protein when they were young also increased their life spans, and longevity drugs resveratrol and rapamycin appeared to induce the same cellular consequences. Mitochondria have their own genomes, but most of the proteins that are necessary for mitochondrial function are encoded by the cells they reside in, making signaling between the two vital for cell health. An editorial that was published with the paper noted that "until now, mutations in mitochondrial genes have not been associated with increased health or longevity in mammals. Therefore, the association of a natural variation in the function of MRPs with increased lifespan seems extraordinary." The work appeared in the May 23, 2013, issue of Nature.

Keeping Stem Cells in Limbo

Researchers at the Chinese Peking University discovered a counterintuitive way to make induced pluripotent stem cells (iPSCs), namely by simultaneously expressing factors that each cause a different cell fate when expressed alone. IPSCs currently are generated by expressing a cocktail of so-called pluripotency factors, but several of those factors can be oncogenic, which has been a headache in terms of iPSC safety for clinical use. The Chinese team took the opposite approach, simultaneously expressing factors that would usher cells to become mesoendodermal or ectodermal. Such cells reacted by remaining in a stem cell-like state that is typical of iPSCs. The authors concluded that their findings "suggest that a chemical screen for small molecules that can substitute for OCT4 and SOX2 in directing the corresponding lineage specification would be a novel and feasible strategy to generate iPSCs." The work appeared in the May 23, 2013, issue of Cell.

Blood Test May Identify PPD Candidates

Scientists at Johns Hopkins University School of Medicine have identified two genes whose methylation status predicted women who would develop postpartum depression with high percent accuracy. The authors used a mix of animal and human studies to test the notion that women who are more sensitive to the effects of estrogen, which can cause methylation changes that affect gene expression, would be more likely to develop postpartum depression. They identified genes most likely to be affected by methylation changes in the hippocampus, a brain region involved in depression. Because estrogen acts throughout the body, they were able to test the methylation status of the genes they identified in blood samples from pregnant women. They found that their candidate genes were more strongly methylated during pregnancy in women who ultimately developed postpartum depression after giving birth. "DNA methylation patterns related to hippocampal synaptic plasticity," they concluded, "may be of etiological importance to [postpartum depression]." The work appeared in the May 21, 2013, issue of Molecular Psychiatry.

Rare Genetic Variants: No There There

Scientists from the British Queen Mary University have concluded that rare genetic variants are unlikely to be behind unexplained heritability of diseases. In their study, the authors conducted detailed sequencing of 25 risk genes for six autoimmune diseases, namely autoimmune thyroid disease, celiac disease, Crohn's disease, psoriasis, multiple sclerosis and Type I diabetes. To date, sequencing studies have been unable to account for all of the genetic risk of those diseases. One theory is that there are rare mutations in risk genes that are not picked up by current sequencing methods, and so the authors sequenced the risk genes in greater depth to see whether they could find such rare genetic variants. They concluded, however, that such rare genetic variants could explain very little of the missing heritability. They concluded that missing heritability "may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common variant loci of weak effect." Their study was published in the May 23, 2013, issue of Nature.

– By Anette Breindl, Science Editor