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by David Mitchell, University of Georgia Temperature-sensitive growth and transcriptomic responses of the Fd-Irp9-OE lines. Researchers at the University of Georgia have identified a promising approach to addressing a longstanding challenge for plant geneticists: balancing disease resistance and growth in plants. The breakthrough could help protect plants from disease in the future while also promoting higher biomass yields to support sustainable food supplies for both humans and animals, production of biofuels and lumber, and more, according to the new study. The paper is published in The Plant Cell journal. "Combating pathogens has been a top challenge in agriculture," said C.J. Tsai, corresponding author of the study and a professor in UGA's Warnell School of Forestry and Natural Resources and Franklin College of Arts and Sciences. "Solutions that balance disease resistance and growth are much needed, especially with the ever-increasing disease pressure due to climate change." Salicylic acid is a well-known plant hormone that plays a vital role in enhancing disease resistance and tolerating stressors like extreme temperatures. Increased salicylic acid levels, however, typically suppress plant growth, making it difficult to implement salicylic acid-based disease management in agriculture. Previous studies attempting to genetically modify plants to increase production of the acid faced obstacles. A few years ago, members of Tsai's lab demonstrated salicylic acid's impact on stress and disease resistance in poplar trees without compromising the plant's growth. They applied this same strategy to the model plant in the new study, the thale cress, creating a new version of the plant with an added gene and increased levels of salicylic acid. At first, the researchers didn't notice much of a growth tradeoff. "We thought maybe the tradeoff had to do with how the salicylic acid increase was engineered," Tsai said. "Then suddenly we'd have a batch of plants that were really tiny. We didn't know what was going on. We ran a large experiment over the winter holiday, thinking that we'd take a break and let our plants grow." After their break, the researchers returned again to smaller-than-normal plants. "It was so frustrating. Then, I was in my hot yoga studio that cold January day, and it just struck me," Tsai said. "It had something to do with the winter." Digging through their notes, the researchers saw a correlation—colder temperatures and colder (tap) water for the plants typically resulted in smaller plant growth. In the present study, the researchers mitigated the impacts of the temperature by modifying specific cold-regulated genes involved in the temperature response. These genes help protect the plant from stressors like low temperatures or drought. But Tsai and her team realized the cold-regulated genes responded negatively to the salicylic acid meant to protect the plant against disease. By "severing" the salicylic acid-responsiveness of these genes, the plants were able to maintain normal growth even with elevated acid levels. "In many cases, we saw improved growth," Tsai said. Characterization of the Arabidopsis Fd-Irp9-OE lines. Discover the latest in science, tech, and space with over 100,000 subscribers who rely on Phys.org for daily insights. Sign up for our free newsletter and get updates on breakthroughs, innovations, and research that matter—daily or weekly. This discovery could have significant implications for crop productivity. Salicylic acid-based strategies have long been known to enhance resistance to pests and pathogens, but practical applications were hindered by the reduction in yield. This study offers a method to separate growth suppression from the defense response, opening the door to use both salicylic acid and cold-regulated genes in agriculture without compromising crop success. The team is already expanding its research by testing the approach on other crops like alfalfa, the "queen of forages." The researchers will test the plant's ability to grow with limited water and nutrient supply. If successful, the technology promises to generate climate-resilient crops. Co-authors on the paper include María Ortega, Rhodesia Celoy, Francisco Chacon, Yinan Yuan, Liang-Jiao Xue, Saurabh Pandey, MaKenzie Drowns and Brian Kvitko. This case study was sponsored by Ligand Pharmaceuticals
New salicylic acid-based strategy could balance disease resistance with plant growth
Salicylic acid enhances disease resistance—until now, that came at a cost
Subscribe New technology may enable farmers to keep plants safe from pests while not compromising growth
Captisol-enabled Contrast Media with Reduced Renal Toxicity in Development
The medical imaging market relies heavily on contrast media, injected into patients to increase the contrast of bodily structures in images and improve diagnostic examinations. In radiographic imaging procedures, iodinated contrast agents can greatly enhance X-rays or computed tomography (CT) images. But many contrast agents carry with them the risk of nephrotoxicity, or renal toxicity, for patients with significant and lingering kidney issues. This risk can lead to the need for renal replacement therapy, or result in rehospitalization and even death. Currently many scientists are searching for ways to develop a more kidney-safe contrast agent for this subgroup of patients. Ligand’s Captisol-enabled iohexol is poised to offer a new opportunity for the diagnostic imaging market.
The Risks of Contrast to Certain Patients
Contrast-induced acute kidney injury (CI-AKI) is one of the most important risks associated with the use of contrast media in diagnostic imaging, as well as procedures that rely on contrast, such as percutaneous coronary interventions (PCI).1 While the many definitions of CI-AKI vary, it is generally considered to be an increase of more than 0.5 mg per deciliter in the serum creatinine level following contrast media administration. CI-AKI signals that a severe decline in kidney function may develop within
72 hours after contrast is injected.
The incidence of CI-AKI varies widely. It is possible for CI-AKI to occur in every patient that has been injected with iodinated contrast, but for those with relatively healthy kidneys the injury may never present as clinical, resulting in no lasting severe consequences. However, patients with a history of chronic kidney disease, diabetic nephropathy and other risk factors face the possibility of more hospitalization, increased healthcare costs, the need for renal replacement therapy or worse, death. While the overall rate of CI-AKI has generally trended downward in recent years, it still remains a significant risk for a subgroup of patients; even routine cardiac procedures using average doses of iodinated contrast can have damaging effects over time.
The Need to Make Contrast Agents Safer for Kidneys
Iodinated contrast agents are highly water-soluble and carbon-based, with the most common types used today either iso-osmolar iodixanol or low-osmolar nonionic monomers (iohexol, iomeprol, iopamidol, iopromide, ioversol, ioxilan). It is thought that the higher the osmolality or the particle concentration in the contrast solution, the greater the vascular symptoms of warmth and pain during injection, as well as CI-AKI.2 There may be stasis of contrast within the kidneys after intravenous procedures are completed, and in patients with CKD and diabetes, there have been reports of nephrograms showing contrast media within the kidneys up to eight days after it was administered.3
The primary strategies of reducing this risk for patients are to select less toxic iodinated contrast agents and to use doses as low as reasonably achievable (ALARA). But in patients with high-risk profiles, there is no absolute safe limit of contrast dosage. In a 2016 study, it was reported there were no adjunctive pharmaceuticals available to have proven effective at preventing or treating CI-AKI.4
The Development of Captisol-enabled Iohexol
The U.S. market for imaging with iodinated contrast agents is estimated at 20 million procedures per year, representing approximately $1.5 billion in annual sales,5 and it is estimated that one-fourth of those who undergo contrast-enhanced imaging are at risk for renal damage.6 With this in mind, a team of scientists at Verrow Pharmaceuticals (acquired by Ligand Pharmaceuticals in January 2018) has studied the effects of reformulating iohexol (the most widely used iodinated contrast agent) with Ligand’s patented Captisol-modified cyclodextrin (sulfobutylether-β-cyclodextrin, or SBECD), which is used to solubilize insoluble drugs for IV injections and improves stability, bioavailability and dosing of active pharmaceutical ingredients.
Verrow’s preclinical studies demonstrated that when SBECD is added to iohexol that has been administered to rodents, significant reductions occur in tubular dilation, vacuolization and loss of brush border. Serum creatinine levels in the mice group were observed to increase after contrast administration and then mitigated by the addition of SBECD, and while rats did not show the same increase in serum creatinine, they showed a significant functional benefit of SBECD. The combined solution showed reduced kidney injury to rodents from contrast doses similar to those used in clinical human settings. The addition of SBECD also showed no adverse effects, instead acting protectively and blocking damage to the kidney.
Further development of this new formulation, or Captisol-enabled iohexol, is now underway at Ligand Pharmaceuticals. The goal is to leverage Captisol technology with iohexol (trademarked as Omnipaque by GE Healthcare) to create “kidney-safe” contrast agents for use in diagnostic imaging as well as for interventional procedures, and any other uses of iodinated contrast agents. With a large potential market and lack of viable alternative options for reducing the risk for CI-AKI, the Captisol-enabled iohexol program is anticipated to potentially establish a new safety standard in the clinical use of iodinated contrast agents.
