Nicotinamide

THURSDAY, Aug. 8, 2024 -- That vape pen might contain something even worse than nicotine, new research warns. Tobacco companies may be trying to duck federal restrictions on vaping products by replacing nicotine with “nicotine analogs” -- related chemicals that have similar properties but unknown health effects, researchers report. “Vaping products containing nicotine are subject to federal laws that prohibit sales to people under the age of 21,” explained researcher Dr. Sairam Jabba , a toxicologist at Duke University School of Medicine, in Durham, N.C. “Nicotine analogs are currently not subject to the FDA process and have not been studied for their health effects.” “It’s possible manufacturers are attempting to avoid FDA tobacco regulation,” Jabba added in a Duke news release. A lab analysis of nicotine analog vapes sold in the United States also “found significant and concerning inaccuracies in the ingredients these products claim to contain and what they actually contain,” Jabba said. For example, a vaping brand called Spree Bar, which comes in at least nine flavors, is listed as containing 5% 6-methyl nicotine, researchers said. A nicotine analog, 6-methyl nicotine has been shown in rodent experiments to be far more potent in targeting the brain’s nicotine receptors, researchers noted. It’s also more toxic than nicotine. Analysis of the Spree Bar products found they contained 88% less 6-methyl nicotine than labeled. They also contained an artificial sweetener up to 13,000 times sweeter than table sugar and an artificial coolant that mimics menthol. Another analog called nicotinamide is being marketed as targeting the same brain receptors as nicotine, even though evidence has shown it doesn’t bind to those receptors, researchers said. E-cigarettes labeled as containing nicotinamide -- Nixotine, Nixodine, Nixamide and Nic-Safe -- had levels lower than their labels indicated, and were combined with undisclosed amounts of 6-methyl nicotine, researchers found. “These products appear to be designed to circumvent the laws and regulations in place to protect people -- especially children -- from the harmful effects of smoking and tobacco use,” said co-senior researcher Sven Eric Jordt , research project director with the Yale Tobacco Center of Regulatory Science. “We do not know what these chemicals do when they are heated and inhaled,” Jordt stressed. “These are questions that should be answered before we allow products on the market.” In late May, a coalition of anti-tobacco groups warned the U.S. Food and Drug Administration of at least three nicotine analog products being sold in the United States. Two of the products, Spree Bar and a snuff made by Outlaw Dip Co., argue on web sites and in promotional videos that their products are not subject to FDA regulation, their letter to FDA Commissioner Dr. Robert Califf noted. However, the promotional materials also promise the same sort of effects from nicotine analogs that people get from actual nicotine, the letter added. The letter quotes Spree Bar promotional materials as promising that the product “provides the same satisfaction, pleasure and enjoyment as traditional tobacco products and nicotine e-cigarettes.” The FDA letter was co-signed by the American Cancer Society Cancer Action Network, American Heart Association, American Lung Association, Campaign for Tobacco-Free Kids, Parents Against Vaping E-cigarettes and Truth Initiative. The research was published Aug. 7 in the Journal of the American Medical Association . Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

A new study identifies NLRC5 as an innate immune sensor that plays a crucial role in PANoptotic cell death -- making it a key therapeutic target. The innate immune system is responsible for protecting the human body from threats that could cause disease or infection. The system relies on innate immune sensors to detect and transmit signals about these threats. One of the key innate immune strategies to respond to threats is through cell death. New research from St. Jude Children's Research Hospital discovered that NLRC5 plays a previously unknown role as an innate immune sensor, triggering cell death. The findings, published in Cell, show how NLRC5 drives PANoptosis, a prominent type of inflammatory cell death. This understanding has implications for the development of therapeutics that target NLRC5 for the treatment of infections, inflammatory diseases and aging. Depending on the threat, innate immune sensors can assemble complexes such as inflammasomes or PANoptosomes. The inflammasome can be thought of like an emergency broadcast system that is activated quickly, while the PANoptosome is more like an emergency response unit that generally integrates more signals and components to respond to the threat. How innate immune sensors work -- what triggers them to act -- has been a mystery, which researchers have been chipping away at for decades. Nucleotide-binding oligomerization domain-like receptors (NLRs) are a large family of important molecules involved in inflammatory signaling. They are generally thought to function as innate immune sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential in energy production, triggers NLRC5-mediated cell death through PANoptosis. "One of the biggest questions in the fields of immunology and innate immunity is what the various members of the NLR family are sensing, and what their functions are," said corresponding author Thirumala-Devi Kanneganti, PhD, St. Jude Department of Immunology vice chair. "NLRC5 was an enigmatic molecule, but now we have the answer -- it is acting as an innate immune sensor and cell death regulator, driving inflammatory cell death, PANoptosis, by forming a complex." Identifying the NLRC5 trigger Scientists in the Kanneganti lab conducted a rigorous screen to get to the bottom of what threats trigger NLRC5. This included looking at pathogens such as bacteria and viruses, as well as pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) that can be released by or mimic an infection or the cause of an injury or illness, as well as other danger signals such as cytokines (immune signaling molecules). The researchers also looked at heme, the component of hemoglobin responsible for carrying oxygen. Infections or disease can cause red blood cells to rupture in a process called hemolysis. This releases hemoglobin into the bloodstream. When hemoglobin breaks down into its components, it releases free heme, which is known to cause significant inflammation and organ damage. The researchers tested many different combinations of pathogens, PAMPs and DAMPs to see if NLRC5 was required for a response. "Among all the combinations we tested, we identified that the combination of heme plus PAMPs or cytokines specifically induces NLRC5-dependent inflammatory cell death, PANoptosis," said co-first author Balamurugan Sundaram, PhD, St. Jude Department of Immunology. "Our results showed for the first time that NLRC5 is central to responses to hemolysis, which can occur during infections, inflammatory diseases and cancers." Energy depletion triggers NLRC5 function Upon identifying the heme-containing PAMP, DAMP and cytokine combinations that trigger NLRC5-dependent inflammatory cell death, the researchers further investigated how NLRC5 is regulated. They found that NAD levels drive NLRC5 protein expression. If NAD is depleted, that sounds an alarm that there is a threat the immune system should recognize. The researchers found that depletion of NAD is sensed by NLRC5, triggering PANoptosis. "By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis," said co-first author Nagakannan Pandian, PhD, St. Jude Department of Immunology. "Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases." The researchers also discovered that NLRC5 is in an NLR network with NLRP12, which come together with other cell death molecules and form an NLRC5-PANoptosome complex that triggers inflammatory cell death. The finding builds on previous research by the Kanneganti lab showcasing the role of NLRP12 in PANoptosis. A promising target for therapeutic development NLRs are associated with diseases related to infection, inflammation, cancers and aging. This makes them intriguing targets for the development of novel therapeutics. The work of the Kanneganti lab shows that deleting Nlrc5 can provide protection against inflammatory cell death through PANoptosis and prevent disease pathology in hemolytic and inflammatory disease models, making NLRC5 an exciting therapeutic prospect. "The fundamental knowledge that we have gained into how innate immune sensing works can be translated to numerous diseases and conditions," Kanneganti said. "Aging, infectious disease, inflammatory disorders -- things for which there are no targeted therapies, this could be an option." Authors and funding The study's other authors are Emily Alonzo, Department of Research and Development at Cell Signaling Technology; and Hee Jin Kim, Hadia Abdelaal, Omkar Indari, Roman Sarkar, Rebecca Tweedell, Jonathan Klein, Shondra Pruett-Miller and Peter Vogel, all of St. Jude, and Raghvendra Mall, formerly of St. Jude now of the Technology Innovation Institute, Abu Dhabi. The study was supported by grants from the National Institutes of Health (AI101935, AI124346, AI160179, AR056296 and CA253095) and ALSAC, the fundraising and awareness organization of St. Jude.