Peripheral and central galactose/β-galactoside-related alterations in ischemic stroke: Clinical associations of circulating LPH and experimental evidence for Glb1 and galectin-3
This study identifies circulating lactase-phlorizin hydrolase (LPH) as a promising peripheral biomarker for acute ischemic stroke and demonstrates that central inhibition of Glb1 and galectin-3 provides synergistic neuroprotection against ischemic neuronal injury.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
Stroke is a sudden, devastating event where blood flow to part of the brain is cut off, starving brain cells of oxygen and causing them to die. For decades, scientists have focused heavily on how the brain handles sugar, specifically glucose, as the primary fuel for these cells. When that fuel supply is blocked, the brain's energy systems collapse, leading to injury. However, the brain is a complex chemical factory, and recent research suggests that when the main fuel line is cut, other, less obvious chemical pathways also go haywire. One such pathway involves galactose, a type of sugar found in milk and other foods, and the specific enzymes that break it down. While we know these sugars are vital for digestion and cellular structure, their role during a stroke has remained a mystery. Understanding how these specific chemical processes change during a stroke could reveal new ways to diagnose the event quickly or protect the brain from lasting damage.
A team of researchers at the Affiliated Hospital of Guizhou Medical University set out to map these hidden chemical changes. They approached the problem from two angles: looking at what happens in the blood circulating through the body, and examining what happens inside the brain tissue itself. Their goal was to find a signal in the blood that could act as a warning sign for stroke, and to identify specific proteins inside the brain that might be making the injury worse. By connecting these two perspectives, they hoped to uncover a clearer picture of the biological chaos that follows a stroke.
The researchers began by taking blood samples from patients who had just suffered an acute ischemic stroke and comparing them to samples from healthy people. Using advanced chemical analysis, they scanned the blood for thousands of different molecules to see which ones were behaving differently. They found that the levels of a specific protein called lactase-phlorizin hydrolase, or LPH, were significantly higher in the stroke patients. LPH is an enzyme usually found in the small intestine, where it helps break down lactose, the sugar in milk, into simpler sugars the body can use. Finding this intestinal enzyme floating in high amounts in the blood of stroke patients was unexpected. When the team tested this finding in a larger group of nearly 2,000 people from the community, they confirmed that higher levels of LPH in the blood were strongly linked to a history of stroke, even after accounting for common risk factors like high blood pressure and diabetes. This suggests that LPH could serve as a new type of biological marker, a measurable sign in the blood that helps doctors identify stroke patients.
While the blood told one part of the story, the brain told another. The researchers turned their attention to two specific proteins found inside brain cells: one called Glb1, which helps break down complex sugar structures inside the cell's recycling centers, and another called galectin-3, which is involved in inflammation and tissue repair. In healthy brains, these proteins are present at normal levels. However, in rats that had suffered a simulated stroke, the researchers found that both Glb1 and galectin-3 were produced in much larger quantities. This surge happened alongside a rise in harmful oxidative stress, a condition where damaging molecules build up and destroy cell structures. The team suspected that these two proteins, while trying to help, might actually be contributing to the damage.
To test this idea, the scientists designed a series of experiments where they blocked the activity of these proteins. In the rats, they used a drug to stop galectin-3 from working and a genetic technique to reduce the amount of Glb1. They found that stopping either protein on its own helped protect the brain. The rats that received the treatment had smaller areas of dead brain tissue, showed fewer signs of cell death, and recovered better from the physical damage of the stroke. The protection was even more significant when the researchers blocked both proteins at the same time. The combined treatment resulted in the smallest areas of brain damage and the best neurological recovery, suggesting that these two proteins work together to worsen the injury, and that stopping both offers the best chance for protection.
The study also looked at individual brain cells in a dish that were deprived of oxygen and sugar, mimicking the conditions of a stroke. Just like in the rats, these cells produced more Glb1 and galectin-3 when stressed. When the researchers blocked these proteins, the cells survived better, produced less of the harmful oxidative stress, and were less likely to die. This confirmed that the protective effect seen in the animals was happening directly within the brain cells themselves. The researchers noted that while the two proteins are linked in the brain's chemical network, blocking one did not automatically stop the other from being produced. This means they likely act through different mechanisms that converge on the same damaging outcome, rather than one simply turning the other on.
The findings offer a dual perspective on how the body reacts to a stroke. On the outside, the blood carries a signal in the form of elevated LPH, which could help doctors identify the event more accurately. On the inside, the brain cells are overwhelmed by an overproduction of Glb1 and galectin-3, which drives further injury. While the study does not prove that LPH causes the stroke or that blocking these proteins will cure it in humans, it provides strong evidence that these specific biological changes are central to the problem. The work suggests that future treatments might focus on calming these specific protein responses to save more brain tissue, while new blood tests could use LPH levels to help diagnose patients faster. The research highlights that understanding the full chemical landscape of a stroke, from the gut to the brain, is essential for developing better ways to treat this life-altering condition.
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