In a groundbreaking study poised to reshape the landscape of inflammatory bowel disease (IBD) treatment, researchers at the University of Louisville have elucidated the molecular mechanisms by which a natural metabolite derived from dietary sources orchestrates a protective immune response in the gut. IBD, encompassing debilitating conditions such as Crohn’s disease and ulcerative colitis, affects millions globally and is characterized by persistent inflammation and compromised intestinal barrier integrity. The intestinal barrier plays a critical role in maintaining homeostasis by allowing nutrient absorption while preventing the translocation of harmful microbial agents. In patients with IBD, this barrier is disrupted, leading to exacerbated inflammation and tissue injury.

Central to this new discovery is urolithin A (UroA), a microbial metabolite produced in the human gut following the ingestion of ellagitannin-rich foods such as pomegranates, walnuts, and berries. The research team led by Dr. Venkatakrishna Rao Jala unveiled how UroA selectively activates the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor expressed in various cell types, including those that constitute the intestinal epithelium. Unlike conventional views of AHR as a mediator of toxicological responses to environmental contaminants, this study highlights a nuanced role for AHR signaling in immune modulation and barrier function maintenance.

In their experimental design, investigators employed a combination of cell culture models, intestinal organoids, and human tissue samples from IBD patients to delineate the cellular and molecular pathways engaged by UroA. This comprehensive approach allowed them to pinpoint intestinal epithelial cells as the primary sites of AHR activation by UroA. Activated epithelial AHR, in turn, stimulates the assembly of the NLRP6 inflammasome, a multiprotein complex traditionally associated with inflammatory cytokine maturation and pyroptotic cell death. Contrary to the canonical inflammatory paradigm, NLRP6 activation here initiates a controlled release of protective mediators that promote epithelial repair, mucus production, and antimicrobial peptide secretion, collectively enhancing barrier integrity.

This dualistic nature of inflammasome signaling reveals an elegant example of cellular context-determined outcomes of innate immune pathways. While systemic inflammasome activation is linked to pathological inflammation, its epithelial-specific engagement appears to serve as a homeostatic mechanism preserving mucosal immunity and preventing microbial dysbiosis. This insight furthers our understanding of the immune microenvironment in the gut and challenges existing dogmas that broadly classify inflammatory signaling as detrimental in chronic intestinal diseases.

The exploration of UroA’s mechanism also sheds light on the intricacies of diet-microbiota-host interactions that underpin gut health. Dietary metabolites have emerged as critical modulators of signaling networks that maintain tissue equilibrium. This study positions urolithin A as a pivotal molecular bridge linking dietary intake to cellular defense strategies, mediated through receptor-mediated inflammasome activation. By elucidating this axis, the findings offer a compelling rationale for dietary or microbiota-targeted interventions designed to harness endogenous metabolites for therapeutic benefit.

Importantly, the protective pathway abrogates damage caused by intestinal injury without invoking broad immunosuppression, a common drawback of current IBD therapies that can predispose patients to infections and malignancies. Targeted activation of epithelial AHR by UroA selectively augments mucosal barrier function while modulating local immunity, offering a precision medicine approach with potentially fewer side effects.

From a translational perspective, these insights could catalyze the development of novel therapeutics that mimic or potentiate UroA’s activity, aiming to restore gut barrier homeostasis in individuals suffering from IBD and other gastrointestinal disorders. Unlike systemic immunomodulators, such agents could enhance intrinsic repair mechanisms, reinforcing the mucosal shield against microbial translocation and inflammation relapse.

Furthermore, this research underscores the importance of endothelial and epithelial cellular compartments in orchestrating immune responses that are finely tuned to environmental and nutritional cues. The aryl hydrocarbon receptor emerges as a nodal point integrating extrinsic and intrinsic signals, modulating inflammasome dynamics uniquely in epithelial cells as opposed to immune cells such as macrophages or dendritic cells, where AHR activation may produce opposing outcomes.

The team’s validation using human intestinal biopsies strengthens the clinical relevance of their findings, demonstrating that UroA-induced AHR-NLRP6 activation is not merely an experimental artifact but a genuine biological phenomenon with implications in human disease states. The investigation also highlights the potential inter-individual variability in microbiota capacity to generate UroA, which may influence susceptibility or response to treatment in IBD patients.

Concluding remarks from the lead investigators emphasize the broader implications of delineating this pathway. By distinguishing harmful from beneficial inflammatory cascades, the study advocates for selective immunomodulation strategies that leverage inherent protective mechanisms instead of indiscriminate suppression. This paradigm shift could revolutionize therapeutic approaches, fostering better clinical outcomes and improved quality of life for those affected by chronic intestinal inflammation.

Collectively, these findings mark a significant advance in gut immunology and open new avenues for precision dietary-based therapeutics. The interaction between diet-derived microbial metabolites, host epithelial signaling, and inflammasome activation represents a complex yet promising frontier in combating chronic inflammatory diseases. As our understanding deepens, integrating nutritional sciences with immunopharmacology may yield innovative treatments that redefine gut health maintenance.

Subject of Research: Human tissue samples

Article Title: Urolithin A activates aryl hydrocarbon receptor-NLRP6-mediated pathways in intestinal epithelial cells to modulate mucosal immunity and strengthen gut barrier integrity

News Publication Date: 23-Jun-2026

Web References: http://dx.doi.org/10.1038/s41467-026-73760-3

References: Published in Nature Communications

Image Credits: University of Louisville

Keywords: Human gut microbiota, Metabolism, Metabolomics, Metabolites, Diseases and disorders, Digestive disorders, Inflammatory bowel diseases, Gastrointestinal tract, Gastrointestinal disorders, Inflammasomes

In the ongoing battle against obesity and its associated cardiovascular risks, new scientific insights are shedding light on the complex interplay between weight loss strategies and vascular health. Recent research from the S-LiTE trial, presented in a landmark study by Sandsdal et al., unfolds groundbreaking findings on how exercise and the GLP-1 receptor agonist liraglutide profoundly influence vascular function and systemic inflammation during weight loss maintenance. This investigation not only advances our understanding of therapeutic approaches but also charts a promising path for improving cardiovascular outcomes in individuals struggling with obesity.

Obesity, recognized as a critical driver of cardiovascular disease, involves pathological alterations in the vascular system and chronic low-grade inflammation. These pathological changes elevate the risk of atherosclerosis, hypertension, and ultimately, heart failure. Consequently, effective weight loss maintenance after initial reductions is paramount for sustaining vascular benefits and mitigating long-term health risks. Despite existing weight loss regimens, relapse rates are high, and how these interventions impact vascular integrity during the maintenance phase remains incompletely understood. The S-LiTE trial rigorously targeted this knowledge gap, merging pharmacological and lifestyle components for a nuanced examination.

Exercise has been universally endorsed as a cornerstone intervention in weight management and cardiovascular disease prevention. Its benefits extend beyond simple calorie expenditure, encompassing modulation of endothelial function, arterial stiffness, and inflammatory profiles. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has garnered attention for its potent weight-lowering effects through appetite regulation and metabolic improvements. However, the independent and combined vascular effects of exercise and liraglutide during the maintenance phase after weight loss had yet to be elucidated prior to this study.

The S-LiTE trial meticulously randomized participants who had achieved significant weight reduction to either an exercise program, liraglutide treatment, a combination of both, or placebo, allowing for a comprehensive comparison across groups. Over the course of the trial, vascular health parameters such as carotid artery compliance, endothelial function assessed via flow-mediated dilation, and systemic inflammatory markers including C-reactive protein (CRP) and interleukins were closely monitored. The multidimensional assessment unveiled striking differences attributable to intervention modalities.

Exercise alone was associated with notable improvements in arterial compliance and a favorable reduction in markers of vascular inflammation. The mechanical stimuli generated during physical activity promote shear stress on vessel walls, which in turn enhance nitric oxide bioavailability and endothelial repair mechanisms. These physiological adaptations are critical for maintaining vascular elasticity and preventing atherogenic processes. This study underscores the indispensable role of exercise not just in weight regulation but as a direct modulator of vascular integrity.

Liraglutide, beyond its appetite-suppressant and glycemic control effects, demonstrated intrinsic vascular benefits. The study highlighted liraglutide’s capacity to enhance endothelial function independently of exercise, potentially through GLP-1 receptor-mediated pathways that reduce oxidative stress and inhibit pro-inflammatory signaling cascades. This offers compelling evidence supporting the use of GLP-1 receptor agonists as adjunct therapies in cardiovascular risk reduction within the obese population.

Intriguingly, the combination of exercise and liraglutide yielded additive benefits, with participants exhibiting the most pronounced improvements in vascular compliance and the greatest suppression of inflammatory cytokines. This synergistic effect suggests that the pharmacological and mechanical influences converge on complementary pathways, amplifying the overall vascular protective effect. Such findings advocate for integrative treatment frameworks that leverage both lifestyle and pharmacotherapy in obesity management.

Delving deeper, the study’s prespecified secondary analysis elucidated how these interventions influenced various immune cell populations that are pivotal contributors to vascular inflammation. It was evident that the combined approach modulated monocyte and macrophage activation states, steering them towards anti-inflammatory phenotypes. This immune modulation is instrumental in curbing chronic inflammation and subsequent endothelial dysfunction, which are foundational in the pathogenesis of vascular disease.

Beyond the vascular sphere, the inflammatory milieu impacts insulin sensitivity and adipose tissue dynamics, central to metabolic health. The study posits that improvements in vascular health might interplay with metabolic regulation, facilitating a virtuous cycle of weight loss maintenance and cardiovascular risk attenuation. This holistic perspective on obesity interventions highlights the interconnected nature of metabolism, immunity, and vascular function.

Crucial to real-world applicability, the study design mirrored long-term maintenance conditions, providing practical insights for clinicians. The sustainability of vascular improvements with continued exercise and pharmacological support affirms the need for ongoing adherence and monitoring. Moreover, the tolerability profile and patient-centered outcomes reported provide a realistic framework for incorporating such regimens in routine care.

This research not only emphasizes the potent vascular benefits tied to weight loss maintenance but also brings to light the nuanced biological effects of different modalities. The implications extend beyond cardiovascular disease prevention, touching on broader aspects of healthy aging and quality of life, as vascular health is integral to multiple organ systems. Hence, the S-LiTE trial’s findings hold substantial promise for shaping future clinical guidelines.

In the broader context of obesity treatment paradigms, these insights challenge the notion that weight loss alone is sufficient. Instead, they advocate for multidimensional interventions addressing vascular function and inflammation, which are crucial mediators of obesity-related morbidity. Such transformations in therapeutic strategies could pivot the field towards more personalized and mechanistically informed approaches.

While the study is robust, the authors acknowledge limitations including the homogeneity of the cohort and potential confounders inherent to lifestyle interventions. Future investigations are warranted to explore molecular signaling pathways in greater detail, diverse populations, and longer-term cardiovascular outcomes. Additionally, integrating imaging modalities and biomarker profiling could refine our understanding of treatment impacts at the microvascular level.

On a scientific and societal level, the S-LiTE trial represents a milestone in conceptualizing weight loss maintenance not simply as weight stabilization but as an active process with profound systemic effects. Public health strategies might evolve to promote combined regimens, potentially alleviating the healthcare burden posed by obesity-related vascular diseases. This research, therefore, stands at the confluence of basic science, clinical innovation, and health policy.

The findings from Sandsdal and colleagues’ work resonate with an emerging narrative in metabolic medicine: holistic, multimodal approaches yield superior benefits than isolated interventions. With obesity prevalence continuing to climb globally, translating these findings into accessible, scalable solutions remains both a challenge and an imperative. The S-LiTE trial ignites hope for more effective, durable solutions to one of the most pressing health crises of our time.

In summary, the S-LiTE trial reveals that exercise and liraglutide individually and synergistically improve vascular health and reduce inflammation during weight loss maintenance. This study offers compelling evidence for the inclusion of GLP-1 receptor agonists alongside structured exercise programs to sustain cardiovascular health in individuals maintaining weight loss. These innovative insights redefine obesity treatment and open new avenues for reducing the global burden of cardiovascular disease through integrated, targeted therapeutic strategies.

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Subject of Research: Effects of exercise and GLP-1 receptor agonist liraglutide on vascular health and inflammation during weight loss maintenance.

Article Title: Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial.

Article References:
Sandsdal, R.M., Holt, J., Alkhefagie, H.G.A. et al. Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial. Nat Metab (2026). https://doi.org/10.1038/s42255-026-01554-4

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s42255-026-01554-4

In a groundbreaking study poised to reshape our understanding of Parkinson’s disease (PD), researchers have unveiled a complex molecular mechanism linking metabolic stress to the disruption of circadian rhythms, with far-reaching implications for neurodegenerative disorders. This deep dive into cellular bioenergetics identifies a glucose-responsive oscillation involving the AMP-activated protein kinase (AMPK), ten-eleven translocation methylcytosine dioxygenase 2 (TET2), and 5-hydroxymethylcytosine (5hmC) axis as a pivotal mediator of metabolic stress responses in the brain. The discovery connects metabolic alterations directly to circadian transcriptional regulation, thereby illuminating previously obscure pathways influencing the onset and progression of Parkinson’s disease.

At the heart of this research lies the energy-sensing enzyme AMPK, a master regulator of cellular metabolism that responds dynamically to changes in cellular energy levels, especially glucose availability. AMPK’s role extends beyond energy balance; it modulates numerous signaling pathways critical for maintaining cellular homeostasis. When glucose levels fluctuate, AMPK activity adjusts accordingly, triggering a cascade of epigenetic modifications mediated by TET2, an enzyme known for its involvement in DNA demethylation and gene expression regulation through oxidative modification of 5-methylcytosine. This AMPK-TET2 interaction sets the stage for rhythmic changes in 5hmC, a key epigenetic mark that fine-tunes circadian gene expression.

The circadian clock is a complex transcriptional network orchestrating daily physiological and behavioral rhythms. Its disruption has been increasingly implicated in neurodegenerative conditions, yet the molecular underpinnings linking metabolism, circadian dysregulation, and neuronal vulnerability have remained elusive. The researchers’ demonstration that metabolic stress-induced AMPK activation regulates TET2-dependent 5hmC oscillations provides a compelling mechanistic bridge. Through this mechanism, energy fluctuations dynamically shape the transcription of circadian genes, potentially disturbing neuronal homeostasis and contributing to PD pathogenesis.

This study utilized a combination of cutting-edge genomic, epigenomic, and proteomic techniques to unravel the dynamics of the AMPK-TET2-5hmC circuit. High-resolution temporal profiling revealed that the oscillations of 5hmC marks at key circadian gene loci are not static but fluctuate in response to metabolic cues. These fluctuations integrate signals of cellular energy status and translate them into rhythmic transcriptional outputs. Importantly, the investigators found that these oscillatory patterns are disrupted in experimental models of Parkinson’s disease, suggesting that the fidelity of metabolic circadian signaling is compromised in neurodegeneration.

A significant aspect of the findings is the direct link between glucose availability and neuronal epigenetic regulation. Metabolic stress, often characterized by reduced glucose uptake or utilization, is a hallmark of aging and neurodegenerative disease states. The AMPK-TET2-5hmC axis serves as a metabolic sensor and effector that translates glucose scarcity into epigenetic reprogramming, thus influencing gene networks that sustain neuronal survival and function. This axis might represent a critical checkpoint where metabolic perturbations exert long-lasting effects on the neuronal epigenome and transcriptome, thereby driving PD progression.

One of the most intriguing revelations of this research is the bidirectional nature of the relationship between metabolic stress and circadian transcription. Not only does metabolic status influence circadian gene expression via epigenetic modulation, but disruptions in circadian regulation feedback to exacerbate metabolic dysfunction. This feedback loop could create a vicious cycle that accelerates neurodegenerative processes, underscoring the importance of maintaining metabolic and circadian integrity for brain health.

The implications of this study extend beyond basic science, offering exciting therapeutic potential. Targeting the AMPK-TET2-5hmC axis may open new avenues for interventions aimed at restoring metabolic and circadian homeostasis in Parkinson’s disease patients. Pharmacological modulators of AMPK activity or epigenetic editors capable of fine-tuning 5hmC dynamics could serve as innovative strategies to halt or slow neurodegeneration. Moreover, optimizing glucose metabolism through lifestyle or pharmacological means might indirectly preserve epigenetic and circadian function, offering a multi-faceted approach to disease management.

The research also highlights the importance of integrating metabolic and epigenetic perspectives to fully capture the complexity of neurodegenerative diseases. Traditional approaches focusing solely on genetic or protein dysfunction have fallen short in explaining the multifactorial etiology and progression of Parkinson’s disease. By illuminating the interplay between energy metabolism and epigenetic regulation, this study sets a new paradigm that could drive future research towards more holistic models of brain pathology.

In addition to elucidating molecular mechanisms, the study provides valuable insights into the temporal dimension of Parkinson’s disease pathology. The rhythmic oscillations of 5hmC marks influenced by glucose and AMPK activity emphasize that timing and metabolic context are crucial factors in disease progression. This may explain the variability in symptom manifestation and disease course among patients and suggests that chronotherapeutic approaches—aligning treatment with the circadian system—could enhance clinical outcomes.

Technologically, the application of multi-omics profiling coupled with advanced computational modeling allowed the researchers to dissect complex regulatory networks with unprecedented precision. Such integrative methodologies are essential for capturing dynamic biological processes that span different molecular layers and timescales. This approach underscores the future direction of biomedical research, where systems biology and temporal dynamics take center stage in unraveling disease mechanisms.

Furthermore, this study draws attention to the overlooked role of 5-hydroxymethylcytosine in the adult brain. Traditionally regarded as mere intermediates in DNA demethylation, 5hmC marks are now recognized as stable epigenetic modifications with distinct regulatory functions. Their oscillatory behavior in response to metabolic cues reveals them as critical mediators linking extracellular environmental factors to nuclear transcriptional machinery, thereby influencing neuronal fate and function.

The association of metabolic stress with circadian dysregulation through the AMPK-TET2-5hmC circuitry also provides a plausible explanation for the observed links between lifestyle factors—such as diet, sleep patterns, and physical activity—and Parkinson’s disease risk. Disruptions in any of these factors can alter glucose metabolism and circadian rhythms, potentially perturbing the delicate balance maintained by this molecular axis and predisposing individuals to neurodegeneration.

Importantly, the study’s findings could redefine biomarker discovery in Parkinson’s disease. Epigenetic oscillations of 5hmC, detectable in neuronal tissues and potentially biofluids, might serve as dynamic indicators of metabolic-circadian health and disease state. This could facilitate earlier diagnosis, tracking of disease progression, and evaluation of therapeutic interventions—ushering in a new era of precision medicine tailored to the metabolic and epigenetic status of patients.

Altogether, the elucidation of the glucose-responsive AMPK-TET2-5hmC oscillation offers a transformative lens through which to understand the intersection of metabolism, epigenetics, and circadian biology in Parkinson’s disease. By identifying a molecular conduit that links metabolic stress to circadian transcriptional misregulation, this research paves the way for innovative diagnostic and therapeutic strategies. As metabolic and circadian dysfunction climb into prominence as central pathogenic drivers, targeted modulation of this axis may hold the key to altering the trajectory of neurodegenerative diseases for millions worldwide.

This pioneering work heralds a new frontier in neuroscience, where cellular energetics, epigenetic remodeling, and circadian rhythms converge to shape neuronal destiny. Understanding and harnessing these complex oscillatory mechanisms offers unprecedented hope for combating the devastating impacts of Parkinson’s disease—a promise that echoes far beyond this single disorder and resonates with the broader quest to unravel the biological rhythms at the core of human health and disease.

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Subject of Research: The study investigates the molecular mechanism linking metabolic stress, circadian transcriptional regulation, and Parkinson’s disease, focusing on the glucose-responsive AMPK-TET2-5-hydroxymethylcytosine (5hmC) oscillation.

Article Title: Glucose-responsive AMPK-TET2-5hmc oscillation links metabolic stress to circadian transcription and Parkinson’s disease relevance.

Article References: Chu, L., Wang, S., Wang, L. et al. Glucose-responsive AMPK-TET2-5hmc oscillation links metabolic stress to circadian transcription and Parkinson’s disease relevance. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01447-z

Image Credits: AI Generated

The foods people eat every day may have a bigger impact on digestive health than many realize. A large international study has found that eating high amounts of ultraprocessed grain products may increase the risk of developing inflammatory bowel disease, a serious condition that affects millions of people worldwide. The findings were published in the […]

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The patient: A 61-year-old man in Japan

The symptoms: The man visited a hospital because two months earlier, some foods and beverages began to taste extremely unpleasant to him. Over time, more foods had become difficult for him to stomach. Sour and salty flavors were the first to trigger disgust. Oily foods were next, followed by fresh vegetables, cold water and juice, warm water and, finally, sweets.

The man ate less due to the taste aversions, and he unintentionally lost a few pounds. He told doctors at the hospital that he felt lethargic, they wrote in a report of the case.

What happened next: The patient, who was a physician himself, reported that eight years ago, he had been diagnosed with bipolar disorder. For the prior three years, he had been managing the condition with lithium, a mood stabilizer commonly used to treat bipolar disorder.

He was taking a prescribed dosage of 800 milligrams per day and historically hadn't had any unusual side effects. (This is slightly higher than the typical dose recommended for chronic management of bipolar disorder, but that said, doctors may tweak patients' doses based on their individual needs.)

The diagnosis: Doctors performed bloodwork and found that the level of lithium in the patient's blood was 1.28 milliequivalents per liter (mEq/L). Safe levels of lithium are between 0.6 and 1.2 mEq/L; any higher than that can cause a condition called lithium toxicity, which can be fatal if untreated.

When the doctors checked the man's medical records, they found that prior to the onset of his symptoms, the levels of lithium in his blood were between 0.4 and 0.9 mEq/L. In the report, the authors did not investigate the cause of the toxicity, nor did they hypothesize as to why lithium was accumulating in the patient's blood.

The treatment: The doctors told the man to stop taking lithium, and they instead prescribed another mood-stabilizing drug, called valproate. As the lithium levels in his blood dropped, the patient's energy returned and the foods and beverages that previously disgusted him recovered their normal flavors. Notably, this happened in the reverse order that their flavors had changed.

At a follow-up visit one year later, the man was still taking valproate and his symptoms of fatigue and taste changes had not returned.

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What makes the case unique: Although they're uncommon, side effects of lithium use can include confusion, increased thirst, frequent urination, irregular or slow heartbeat, tiredness and weight gain. Rarer side effects include dizziness, headaches, vision problems and heat loss in the arms and legs. Lithium toxicity, also known as lithium intoxication, is known to increase the risk of these adverse symptoms.

Changes in a patient's sense of taste while taking lithium have been recorded in just a handful of reports dating to the 1970s and 1980s. One patient lost the ability to taste salt, while another "noticed a strange and unpleasant taste associated with butter and celery."

Nevertheless, "it has not been generally known that lithium can lose or change taste in some patients," the case report authors wrote. Based on their findings, they suggested that in the future, taste loss or changes in taste perception should be flagged as a potential indicator of mild lithium intoxication.

This article is for informational purposes only and is not meant to offer medical advice.

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Using drugs to induce a hypothermia-like state may slow stroke-related brain damage, according to a new study involving lab animals and human patients.

The study used two existing drugs: the antipsychotic chlorpromazine and the sedative promethazine, called "C+P" when they're used together. This drug combo induced hypothermia and protected brain tissue in mouse and monkey models of stroke.

Additionally, an infusion of C+P was safe in an early trial including 32 human stroke patients, causing no notable side effects. However, no significant improvements in stroke outcomes were reported in a paper describing the results, which was published June 17 in the journal Science Translational Medicine.

More research is needed to determine what benefits C+P treatment may offer stroke patients. But the research sheds new light on the metabolic dynamics believed to be responsible for hypothermia's therapeutic effects, said Dr. Eric Landsness, an assistant professor of neurology at the Washington University School of Medicine in St. Louis who was not involved in the work.

"What's exciting about this study is that it's clear that it's not just the hypothermia, but it's the hypometabolism," said Landsness, who reviewed the paper before it was published.

Brain freeze?

The researchers tested C+P as a therapy for acute ischemic stroke, in which blood flow to the brain is blocked. Ischemic strokes are the most common form of stroke, accounting for over 85% of cases; "acute ischemic stroke" specifically refers to the medical emergency brought about by a sudden loss of blood flow to the brain and corresponding loss of neurologic function.

When blood flow is restored through a therapy called reperfusion treatment, "you can get significant injury from a lot of processes that were set in motion during the ischemia," said Dr. Patrick Lyden, a professor of physiology and neuroscience, neurology, and neurosurgery at the University of Southern California Keck School of Medicine who was not involved in the study.

To protect brain tissue from this double whammy of ischemia and reperfusion injury, some researchers have tried to harness hypothermia, which is "one of the most powerful ways of protecting the brain that we've ever studied in lab animals," Lyden told Live Science. "It's the standard by which all other brain protectants are measured."

In hypothermia, body temperature drops below 95 degrees Fahrenheit (35 degrees Celsius). Under normal circumstances, this can be very dangerous because the cold can slow down the heart and nervous system to the point that the body's cardiac and respiratory systems fail.

But one of the biggest theories for why hypothermia works in a therapeutic context is that it slows down our metabolism, similar to what's seen in animals during hibernation, Lyden said. "Because the metabolism is slowed, the death process in the brain is also slowed down."

Therapeutic hypothermia can protect the human brain following cardiac arrest, and it is also sometimes used to treat newborns with hypoxic ischemic encephalopathy, an injury that blocks blood and oxygen to the brain around the time of birth. However, studies of hypothermia in adult stroke patients have been less successful, Lyden said.

The C+P approach may be a more effective way to slow metabolism in stroke patients, the researchers hypothesized. In previous experiments, C+P reduced neuroinflammation in rodent models of stroke, possibly through changes in metabolic activity independent of hypothermia.

In the new study, the treatment was compared with two other methods of reducing core temperature in mice: a different drug, called adenosine 5'-monophosphate, and surface cooling using cold water and ice packs. While all three approaches induced hypothermia in the mice, only C+P treatment reduced their overall oxygen consumption and energy expenditure, two important indicators of slowed metabolism.

The paper highlights metabolism as more than a mere secondary effect of hypothermia, Landsness said; it's a process worth studying in its own right.

In mice, C+P treatment reduced the burning of sugar by the brain and brown fat, which burns fuel to generate heat. The treatment was also associated with less brain tissue damage and lactate accumulation, which can drive cell death, after stroke. These effects were also observed in rhesus monkeys treated with C+P.

According to the small safety trial with humans, the metabolic effects of C+P appear to extend to people.

The researchers measured lower levels of metabolism-associated proteins in the blood of patients who received the highest dose of the treatment tested. These were also the only patients to experience a significant decrease in body temperature at four hours after treatment, although their temperatures never dipped into true hypothermia. (Temperatures did fall that dramatically in the mice and monkeys.)

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In people, C+P infusion did not reduce the degree of brain damage seen 72 hours after treatment, nor did it affect the participants' ability to perform daily activities without assistance after 90 days. Alongside the C+P treatment, the patients had also received standard reperfusion therapies.

The study authors, based at Capital Medical University in Beijing, did not respond to Live Science's request for comment. In their paper, they wrote that future trials could potentially establish the protective value of the C+P treatment in stroke.

In the current study, C+P did not trigger notable side effects in humans, but Lyden worried that the medications may still pose a risk of worrying effects. The two drugs could potentially interact in ways that cause symptoms like muscle spasms, seizures or changes in heart rhythm, for example. For that reason, it may be best to find different drugs that still slow metabolism but don't come with those risks, Lyden suggested.

To find an alternative to the C+P regimen, researchers will need a better sense of how the drugs exert their effects. The new paper "happened to fall upon a drug [combo] that happens to induce hypothermia and hypometabolism, but we don't necessarily know why," Landsness said. His lab is studying the neural circuits involved in hypothermia and hypometabolism, which could reveal new therapeutic targets.

This article is for informational purposes only and is not meant to offer medical advice.

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In an extremely odd case, a single 79-year-old patient was granted early access to Eli Lilly's powerful, still-experimental obesity drug retatrutide through the Food and Drug Administration's "compassionate use" program—raising immediate questions if that sole patient is President Donald Trump, according to a report by Stat News.

Lilly's retatrutide is a highly anticipated next-generation obesity drug that targets GIP and glucagon hormones in addition to GLP-1. It is currently in late-stage trials to treat obesity, diabetes, sleep apnea, and other conditions. Data from a Phase 3 trial that Lilly released in May indicates that patients with obesity (but without diabetes) who took the drug for 80 weeks lost 28 percent of their weight, an amount comparable to bariatric surgery.

Millions of Americans with obesity are eager to get the drug, with options being limited so far to enrolling in a clinical trial or trying to obtain it by dodgy methods.

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