New Treatment Target for Diabetes Complications: tRF-3001a
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New Treatment Target for Diabetes Complications: tRF-3001a
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New Treatment Target for Diabetes Complications Discovered: tRF-3001a.
Diabetes is a metabolic disorder characterized by high blood sugar and glucose intolerance. It affects a significant portion of the global population, with over 400 million people diagnosed worldwide.
Prolonged high blood sugar levels can lead to severe damage in various bodily systems, particularly the vascular and nervous systems. Diabetes-related vascular complications are considered the primary causes of end-stage renal failure, blindness, and atherosclerosis, making them major contributors to disability and mortality among diabetic patients.
Furthermore, approximately 50% of diabetic patients suffer from notable neuropathies, resulting in severe damage to sensory neurons, motor neurons, and the autonomic nervous system.
Consequently, the pathogenesis of diabetes is closely intertwined with both vascular dysfunction and neurodegenerative processes.
Currently, the treatment of diabetes and its complications involves strategies such as dietary control, physical exercise, smoking cessation, and medications to manage complications. However, these methods do not entirely reverse or halt the progression of vascular and neurodegenerative complications caused by metabolic memory. Thus, gaining a deeper understanding of the mechanisms underlying vascular and neurological damage is crucial for the development of new targets for diabetes prevention and treatment.
On September 26, 2023, Professor Yan Biao and colleagues from Fudan University published a research paper titled “Hyperglycemia-regulated tRNA-derived fragment tRF-3001a propels neurovascular dysfunction in diabetic mice” in the journal *Cell Reports Medicine*.
This study identifies a specific transfer RNA-derived fragment (tRF), known as tRF-3001a, which exhibits significantly elevated expression in diabetes.
Importantly, it is demonstrated that tRF-3001a acts as a regulator of retinal neurovascular dysfunction, offering promise as a novel target for addressing both diabetic vascular complications and neuropathies simultaneously.
Epigenetic mechanisms can regulate gene expression and shape molecular responses within cells without altering DNA sequences, allowing genes to interact with their environment. The pathogenesis of diabetes is highly influenced by environmental factors such as nutritional status, growth factors, and oxidative stress, all of which can disrupt epigenetic mechanisms.
Non-coding RNAs, including microRNAs (miRNAs), piRNAs, small nucleolar RNAs (snoRNAs), and tRNA-derived fragments (tRFs), are crucial players in epigenetic regulatory networks that control gene expression. Among these, tRFs are 13-48nt products generated from precursor or mature tRNAs through ribonuclease cleavage under pathological conditions.
tRFs are involved in multiple biological processes, including gene expression, protein synthesis, and RNA processing. Dysregulation of tRFs is implicated in the pathogenesis of cancer, metabolic disorders, and neurological diseases. Consequently, tRFs are considered promising diagnostic markers and therapeutic targets for human diseases. However, there has been limited research investigating the role of tRFs in the processes of diabetic vascular complications and neuropathies.
The retina, an extension of the central nervous system, is one of the most common sites affected by high blood sugar damage in diabetes. Diabetic retinopathy (DR) is a leading cause of visual impairment among the working-age population and is generally considered a microvascular complication of diabetes, with its diagnosis heavily reliant on the detection of vascular abnormalities. However, a significant proportion of DR patients do not experience substantial improvements in vision. In fact, the pathogenesis of DR is associated with neurodegeneration of the retina, in addition to affecting retinal vascular cells.
Previous studies have shown that retinal neurodegeneration sometimes precedes retinal vascular abnormalities. As a result, it is increasingly recognized that DR represents a neurovascular disease that affects both retinal vascular and neuronal cells.
The neurovascular unit (NVU) comprises vascular cells, glial cells, and neurons, all closely interconnected and collectively responsible for maintaining the structural and functional integrity of the eye, particularly under metabolic stress. Damage to the NVU is a significant event in DR, although the mechanisms behind NVU injury have not been fully elucidated.
In this study, the research team explores the role of tRF-3001a in diabetes-induced retinal neurovascular dysfunction. tRF-3001a is a tRNA-derived fragment with the sequence 5′-ATCCCACCGCTGCCACCA-3′.
The research findings indicate that, in diabetes, tRF-3001a expression levels are significantly upregulated, and reducing tRF-3001a expression can alleviate retinal vascular dysfunction and suppress retinal neurodegeneration. The study further reveals the mechanism by which tRF-3001a regulates retinal neurovascular dysfunction in a manner reminiscent of miRNA action. Additionally, clinical observations demonstrate elevated expression levels of tRF-3001a in aqueous humor samples from DR patients.
Specifically, the downregulation of tRF-3001a inhibits Müller cell activation, suppresses endothelial vasculogenesis, and protects against high glucose-induced damage to retinal ganglion cells. Moreover, reducing tRF-3001a levels can mitigate retinal vascular dysfunction in streptozotocin (STZ)-induced diabetic mice and db/db diabetic mice, inhibit retinal reactive gliosis, promote the survival of retinal ganglion cells, and preserve visual function and visual-guided behaviors. Mechanistically, tRF-3001a modulates neurovascular dysfunction through a miRNA-like mechanism targeting GSK3B. Clinically, elevated expression of tRF-3001a is observed in aqueous humor samples from DR patients. Downregulation of tRF-3001a alleviates high glucose-induced dysfunction in human retinal vascular endothelial cells and Müller cells in vitro, as well as retinal neurovascular dysfunction in C57BL/6J mice induced by DR. Consequently, targeting tRF-3001a-mediated signaling represents a promising strategy for the simultaneous treatment of diabetic vascular complications and neuropathies.
In conclusion, this research suggests that tRF-3001a acts as a regulator of retinal neurovascular dysfunction and is a promising target for addressing both diabetic vascular complications and neuropathies.
New Treatment Target for Diabetes Complications: tRF-3001a
Link to the paper:
[https://doi.org/10.1016/j.xcrm.2023.101209](https://doi.org/10.1016/j.xcrm.2023.101209)
(source:internet, reference only)
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