The study, published in BMC Pharmacology and Toxicology, explores how Pycnogenol, a potent antioxidant derived from French maritime pine bark, mitigates the complex pathophysiology induced by TAA. Through a detailed molecular investigation, the researchers demonstrated that Pycnogenol exerts its protective effects by modulating several cellular signaling pathways simultaneously—addressing oxidative stress, inflammation, and apoptotic mechanisms that collectively drive neurobehavioral and hepatic dysfunction.

Oxidative stress is a primary culprit in TAA toxicity, characterized by excessive reactive oxygen species (ROS) production that damages cellular lipids, proteins, and DNA. Pycnogenol’s rich polyphenolic content enhances endogenous antioxidant defenses by upregulating enzymes like superoxide dismutase (SOD) and catalase, thereby restoring redox balance within affected tissues. This molecular balancing act helps preserve neuronal integrity and ameliorate cognitive impairments seen in the TAA model.

Moreover, neuroinflammation, often triggered by hepatotoxic injury, exacerbates neuronal damage through the release of pro-inflammatory cytokines such as TNF-α and IL-6. The study highlights Pycnogenol’s ability to suppress these inflammatory mediators, likely through the inhibition of nuclear factor kappa B (NF-κB) signaling, a master transcription factor orchestrating inflammatory responses. This dual antioxidant and anti-inflammatory action culminates in marked improvements in behavioral outcomes related to memory, coordination, and locomotor activity.

Hepatic injury manifests through disrupted liver enzymes, lipid peroxidation, and histopathological abnormalities following TAA exposure. Encouragingly, Pycnogenol treatment reversed these detrimental changes, normalizing serum biomarkers like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and promoting hepatocyte regeneration. This underscores the compound’s potential as a hepatoprotective agent in chemical-induced liver damage.

Importantly, the multi-target molecular modulation observed indicates that Pycnogenol does not rely on a single pathway but engages a network of signaling cascades to exert its therapeutic effects. This polypharmacology approach may be particularly advantageous in treating complex diseases where oxidative stress, inflammation, and apoptosis are intertwined, such as neurodegenerative disorders and chronic liver diseases.

The findings raise the possibility of translating these preclinical results into clinical applications, providing a natural adjunct or alternative to conventional treatments that often carry significant side effects. Future investigations exploring optimal dosages, long-term safety, and efficacy in human subjects will be critical to fully harness Pycnogenol’s therapeutic potential.

As our understanding of the intricate molecular mechanisms governing neurobehavioral and hepatic toxicities deepens, such studies highlight the untapped power of phytochemicals like Pycnogenol in combating multifaceted pathologies. This research paves the way for innovative, multi-mechanistic therapeutic strategies that could transform patient outcomes in toxic liver injury and associated neurological complications.

Subject of Research: Neurobehavioral impairment and hepatotoxicity induced by thioacetamide and their attenuation by Pycnogenol via multi-target molecular pathways

Article Title: Pycnogenol attenuates thioacetamide-induced neurobehavioral impairment and hepatotoxicity via multi-target molecular modulation

Article References: Senyayla, S., Hacimuftuoglu, A., Bayram, C. et al. Pycnogenol attenuates thioacetamide-induced neurobehavioral impairment and hepatotoxicity via multi-target molecular modulation. BMC Pharmacol Toxicol 27, 96 (2026). https://doi.org/10.1186/s40360-026-01175-3

Image Credits: AI Generated

DOI: https://doi.org/10.1186/s40360-026-01175-3

Eato belongs to the ABCA family of membrane transporters, proteins integral to maintaining lipid homeostasis by regulating the trafficking of phospholipids across cell membranes. Among these, human homologs such as ABCA1 and ABCA7 have established links to Alzheimer’s disease, underlining the clinical relevance of this protein family in neurodegeneration. The Cornell team’s insights emerged from observing the behavior of Eato-deficient neurons in fruit flies, revealing that neuron survival hinges on the delicate balance Eato maintains in the exposure of a critical "eat-me" signal—phosphatidylserine (PS).

Phosphatidylserine, a phospholipid normally localized to the inner leaflet of the plasma membrane, flips to the cell surface during neuronal stress or apoptosis, serving as an identification flag for phagocytes. These immune cells are responsible for the targeted clearance of dying or damaged neurons, a process that, if improperly regulated, can lead to excessive neuronal loss and exacerbate neurodegenerative pathology. The researchers demonstrated that Eato suppresses premature PS exposure on healthy neurons, thereby preventing their untimely engulfment by phagocytes.

Unexpectedly, the research revealed that removal of Eato from neurons resulted in increased PS surface exposure and subsequent neuron loss. Contrarily, elimination of Eato from phagocytic glial cells led to reduced neuronal degeneration, indicating the protein’s bifunctional influence. This duality suggests Eato not only modulates the suppression of PS exposure within neurons but also facilitates recognition of PS by phagocytes, orchestrating neuron-glia interactions fundamental to brain homeostasis. Such opposing roles compel a reevaluation of ABCA transporters’ functions in neurobiology.

The team utilized sophisticated live imaging and genetically engineered mutations in Drosophila to monitor PS exposure dynamics and phagocytic activity. They identified distinct phenotypic categories ranging from normal neural integrity to degeneration localized within specific brain regions, emphasizing the spatial precision of Eato’s action. Their findings illuminate formerly obscure mechanisms underpinning phagocytosis-driven neurodegeneration and open novel avenues for targeted therapeutic intervention.

Neurodegenerative diseases impose a monumental socioeconomic burden. Alzheimer’s disease alone accounts for approximately $305 billion in care costs annually in the United States, projected to exceed $1 trillion as global demographics shift toward aging populations. Parkinson’s disease similarly strains healthcare systems, with annual costs surpassing $50 billion due to direct medical expenditures and indirect impacts such as lost productivity and caregiver demands. Innovative treatments addressing underlying cellular mechanisms are urgently needed.

By elucidating how Eato governs PS exposure and neuronal fate, the Cornell study provides a credible molecular target for therapies aimed at halting or mitigating neurodegeneration. In principle, drugs designed to sustain appropriate PS localization or modulate phagocyte detection mechanisms might prevent the premature clearance of healthy neurons. This strategy contrasts with traditional approaches that primarily address symptomatic relief rather than disease causation.

Professor Chun Han, leading the research at Cornell’s Weill Institute for Cell and Molecular Biology, highlighted the novelty of these findings. “Eato’s dualistic regulation of PS exposure in both neurons and glia defies prior assumptions about ABCA transporter function,” he stated. This nuanced understanding challenges the simplistic model of PS as an unregulated apoptosis marker, underscoring an active maintenance system in healthy neuronal environments.

The implications extend beyond Alzheimer’s and Parkinson’s diseases, as aberrant phagocytosis is implicated in various neuroinflammatory and degenerative conditions. Understanding the molecular crosstalk between neurons and phagocytes mediated by lipid signals could redefine disease pathogenesis and guide precision medicine efforts.

Importantly, removing PS exposed on Eato-deficient neurons experimentally was found to prevent neuronal degeneration. This suggests that manipulation of lipid signaling pathways holds promise for neuroprotection, potentially allowing for preservation of cognitive and motor functions lost in these devastating disorders.

Moving forward, the study opens intriguing questions about how similar mechanisms operate in mammalian systems and how ABCA transporters coordinate complex lipid signaling across different brain cell types. The intricate balance between protecting neural tissue and enabling its clearance when damaged represents a crucial frontier in neuroscience research.

In summary, the Cornell team’s discovery of Eato’s opposing roles in neurons and phagocytes significantly advances our molecular understanding of neurodegeneration. By highlighting the importance of regulated phosphatidylserine exposure and subsequent phagocytic response, their work lays the foundation for innovative strategies aimed at protecting the brain’s vulnerable cells and slowing the progression of incurable diseases.

Other key contributors to this pioneering work include Bei Wang, Ankita Sarkar, Zixian Huang, Nicolas Vergara Ruiz, Ann T. Yeung, and Rachael Chen, all affiliated with Cornell University’s Weill Institute. Their collective efforts bring us closer to unlocking some of the brain’s most guarded secrets, holding hope for millions affected worldwide.

Subject of Research: Molecular mechanisms of neurodegeneration involving ABCA transporter Eato and phosphatidylserine exposure in neurons and phagocytes.
Article Title: Phagocytosis-driven neurodegeneration through opposing roles of an ABC transporter in neurons and phagocytes
News Publication Date: 12-Mar-2025
Web References:

• Science Advances article
• Han Lab at Cornell University
  Image Credits: Han Lab
  Keywords: Molecular biology, Neurodegeneration, Alzheimer’s disease, Parkinson’s disease, ABCA transporters, Phosphatidylserine, Phagocytosis, Neuron-glia interaction, Lipid signaling

Imagine that you are in your sixties or seventies, and on a brisk walk. Your muscles contract, setting off small waves of calcium and other signaling molecules. In response, your skeletal muscle cells secrete a host of myokines into your bloodstream—molecules such as interleukin-6 (IL-6) and irisin. Meanwhile, your adipose tissue, sensing metabolic demands, releases adipokines that fine-tune insulin sensitivity. Your liver, stirred by changes in blood flow and metabolic substrates, sends out hepatokines such as fibroblast growth factor 21 (FGF21). And your bones, subjected to the forces of gravity and muscle tension, secrete osteocalcin or other osteokines that preserve skeletal integrity. Even your brain—through glial cells or neurons—contributes neurokines that bolster synaptic plasticity. All these exerkines then travel through the bloodstream, coordinating with different organs, collectively pushing back against the harmful effects of age-related stress and inflammation.

It is well known that aging coincides with a series of systemic changes—reduced muscle mass (sarcopenia), diminishing bone density (osteoporosis), elevated inflammation (“inflammaging”), and a decline in mitochondrial quality. The danger is that these changes feed into each other, leading to a spiraling loss of vitality. But the exerkines triggered by regular physical activity can break this vicious cycle. For instance, certain exerkines promote a shift away from chronic inflammation by boosting the production of anti-inflammatory mediators like interleukin-10 (IL-10) and restricting pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α). Others enhance the oxidative capacity of skeletal muscle, reducing the accumulation of reactive oxygen species (ROS) and preventing mitochondrial decay—major contributors to cellular dysfunction in older adults.

Scientists have begun to pinpoint precisely how exerkines exert these protective effects. One factor is the well-known molecule IL-6, which can exhibit pro-inflammatory behavior in certain contexts but acts as an anti-inflammatory signal during and immediately after exercise. Another is irisin, a hormone-like factor that helps convert white adipose tissue into a more metabolically active “beige” fat, raising one’s resting energy expenditure while improving insulin sensitivity and metabolic health. Meanwhile, fibroblast growth factor 21 (FGF21), secreted mainly by the liver, exerts beneficial effects on glucose control and lipid metabolism, thus lowering one’s vulnerability to type 2 diabetes. Myostatin, once considered only a negative regulator of muscle growth, has emerged as a possible modulator of tumor suppression. Apelin, another exerkine, fosters the health of both bone and muscle tissue, helping older bodies withstand the rigors of daily life. And in the brain, molecules like clusterin or glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) can dampen inflammation and shore up neural plasticity, safeguarding cognition in older adults.

At first, it may sound like an astonishing synergy: how can the same physical movement help the heart, bones, muscles, immune system, and even the brain? But the body’s architecture is deeply interconnected, and exerkines serve as the biochemical messengers that tie all these benefits together. Perhaps the clearest example is skeletal muscle, the largest organ by mass in most people, which rapidly communicates with other tissues during a workout. The molecular signals it emits—the myokines—can travel to the liver to promote better fat oxidation, or to the brain to encourage synaptic plasticity. They may also act on the immune cells, fine-tuning the balance between pro-inflammatory and anti-inflammatory signaling. Likewise, adipose tissue secretes adiponectin, which fosters fatty acid oxidation and reduces insulin resistance in muscle and liver, while also modulating inflammatory processes system-wide. This level of cross-organ “conversation” explains why a simple brisk walk or a few sets of resistance exercises per week can lower the risk of so many age-related conditions—from cardiovascular disease and type 2 diabetes to osteoporosis and some cancers.

Given the multiplicity of exerkines, it should be no surprise that different forms of exercise generate distinct benefits. The recommendation for older adults, proposed by various international guidelines, generally includes a combination of resistance training, aerobic exercise, and balance activities. Resistance or weight training stimulates muscle hypertrophy and strength gains, spurring the release of exerkines that specifically promote muscle repair and anabolism. Aerobic exercises like walking, jogging, or cycling, at intensities around 55–70% of maximum heart rate, are associated with improved cardiovascular function, higher levels of beneficial cytokines such as IL-10, and better glycemic control. Balance and flexibility exercises, such as yoga and tai chi, are no less important; they may not generate as high an acute exerkine surge as intense resistance training or cardio, but they do help preserve neuromuscular coordination and reduce the risk of falls—a critical factor in healthy aging.

One of the cornerstones of exerkine research is the notion that improving mitochondrial function is a central mechanism of “exercise as medicine.” With age, mitochondria in cells become less efficient at producing ATP (adenosine triphosphate), and they accumulate oxidative damage. Exercise can mitigate this by increasing the expression of key enzymes like glutathione peroxidase (GPx), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1), which help neutralize free radicals. ROS no longer run rampant, so the negative feedback loop leading to further mitochondrial damage is dampened. Meanwhile, exerkines promote the production of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a major driver of mitochondrial biogenesis. As a result, older individuals who engage in physical activity can regenerate healthier mitochondria, thus powering their cells more effectively. The payoff is less cellular senescence, improved nutrient sensing, and often a reduction in chronic inflammation.

It is important to note that the synergy between exercise and exerkines extends into domains like cognitive function. Regular training fosters a rise in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for neuronal survival, synaptic plasticity, and hippocampal neurogenesis. This helps guard against the cognitive deficits associated with disorders such as Alzheimer’s disease. Some exerkines, such as glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) and platelet factor 4 (CXCL4), have also been implicated in hippocampal neurogenesis, encouraging the generation of new neurons and reversing certain aspects of age-related mental decline. These discoveries resonate strongly with observational data showing that physically active older adults frequently show slower cognitive decline and lower incidence of neurodegenerative conditions.

For those concerned about type 2 diabetes, exercise again steps in with an exerkine-mediated strategy. Muscle contraction not only draws glucose into cells via transporters like GLUT4, it also triggers the release of certain hepatokines from the liver and adipokines from fat that normalize blood sugar levels. FGF21, for instance, fosters insulin sensitivity, while HSP72 (heat shock protein 72) can prevent misfolded protein accumulation in pancreatic beta cells. Even short bursts of activity can drive these beneficial changes. Though many older people worry about whether they can safely engage in vigorous workouts, the research points to moderate, consistent habits—like walking daily or lifting light weights multiple times a week—as enough to catalyze these systemic benefits.

Another striking area of discovery is the way exerkines appear to influence bone health. Osteocalcin, produced by bone in response to the mechanical load from weight-bearing exercise, helps maintain bone mineral density and appears to have metabolic functions that extend beyond bone. It may, for example, improve insulin sensitivity. Meanwhile, molecules such as TGF-β1 and apelin, also upregulated by exercise, can help coordinate bone formation and muscle mass. For older adults whose bones grow increasingly fragile, these factors are a ticket to reduced fracture risk and better musculoskeletal resilience. In some scenarios, the synergy between osteokines and myokines can help accelerate bone healing after injury or surgery, a tremendous boon for those in advanced age.

Add to this the remarkable possibility that exerkines carry at least some anti-cancer properties, and exercise’s significance in health management gains still more luster. Myostatin, ironically known for suppressing muscle growth, has recently been linked to anti-tumor functions in certain tissues, possibly by dampening pathways that drive unchecked proliferation. Irisin, once studied for its effect on adipose tissue browning, also shows promise as an anti-tumor agent in preclinical models, often by boosting the immune system’s detection of malignant cells or by altering local inflammatory signals that help tumors thrive. Even though these studies are preliminary, they open an exciting dimension of research: perhaps a consistent exercise routine could lower both the risk of developing cancer and, in some cases, slow progression for those who already have it.

Despite the avalanche of positive evidence, we must tread carefully. Not all forms or intensities of exercise deliver uniform exerkine responses. Overtraining—exercising too vigorously or too frequently—can create oxidative stress or immune suppression, especially in older individuals who may have other comorbidities. The goal, therefore, is moderation and personalization: designing a plan that taps into the beneficial exerkine output without overwhelming the body’s capacity to recover. Many new areas of research revolve around “exercise mimetics,” compounds that mimic the effect of exerkines by targeting the same molecular pathways. For individuals too frail to exercise adequately, such compounds could theoretically provide the health benefits of a workout. But the nuance is that exercise is not merely a pill to be replaced; it sets in motion large-scale mechanical, neural, and metabolic processes that may not be fully replicated by a single compound or cocktail.

What will the future hold for this intriguing domain of exerkines and anti-aging strategies? One possibility is that health practitioners will monitor exerkine levels in the bloodstream to gauge whether an older adult’s exercise regimen is truly effective. Another is that gene- or cell-based therapies could selectively increase expression of beneficial exerkines, or block “rogue” molecules that hamper healthy aging. As more is uncovered about how these molecules act and interact, a new generation of geriatric medicine could arise, leveraging exerkines to combat conditions as diverse as Alzheimer’s, frailty, and diabetes. Pharmacologists already see exerkines as potential “druggable” targets. For instance, if we can harness the browning effect of irisin safely, we might treat obesity without radical changes in diet. If we can modulate clusterin or BDNF effectively, we might slow cognitive decline. Conversely, controlling overactive inflammatory exerkines in certain autoimmune settings might stave off age-associated autoimmune conditions.

Yet, in the midst of all these futuristic innovations, the core message remains clear: regular movement, even in modest doses, is already our best bet for “turning on” these beneficial exerkines. Where certain pharmaceutical avenues may take years to become safe and widely available, everyday exercise is accessible now, with little risk and abundant upside. Medical experts emphasize that older adults should combine strategies: build in some resistance training to preserve muscle mass and bone density, incorporate aerobic exercise to bolster cardiovascular and metabolic function, and do balance activities to reduce fall risk and maintain neural reflexes. These are not complicated tasks, but the molecular payoffs—in the form of exerkine release—can be profound.

Ultimately, the story of exercise-induced exerkines is one of the most compelling examples of how our bodies are designed for movement, and how that movement orchestrates a symphony of positive biological signals. By activating these signals through conscious, consistent activity, we tap into a powerful, evolution-built mechanism that defends us against the degradations of time. Gone are the days when we could think of exercise merely as a means to burn calories. Instead, each session of walking, resistance training, or mindful balance exercises sets off thousands of molecular changes that can be harnessed to keep us healthier for longer. It is a powerful illustration that our biology wants us to move, and in moving, we coax our cells to produce molecules that can keep the ravages of age at bay.

As researchers continue to refine our understanding, we may see more targeted advice on the most effective exercise “doses,” frequencies, and intensities for stimulating beneficial exerkines. We may also see novel interventions that help older adults overcome barriers to physical activity, from wearable technology that tracks functional movement patterns to community programs aimed at delivering personalized exercise regimens. If further breakthroughs arrive with safe and effective exercise mimetics, so much the better. Yet for now, the basic science underscores a unifying conclusion: exercise remains one of our most potent forms of preventive medicine, not just for the muscle and cardiovascular advantages, but for the invisible molecular crosstalk that might very well determine how gracefully and how long we age.

Subject of Research: Exercise and Exerkines in Anti-Aging and Disease Prevention
Article Title : Exercise and Exerkines: Mechanisms and Roles in Anti-Aging and Disease Prevention
News Publication Date : February 2025
Article Doi References : https://doi.org/10.1016/j.exger.2025.112685
Keywords : Exerkines, Anti-aging, Exercise Physiology, Mitochondrial Function, Muscle Mass, Inflammaging, Cognitive Decline, Metabolic Homeostasis, Bone Density