医学最新文献

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic-pituitary-adrenal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor-mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic-pituitary-adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment-associated diseases, such as Alzheimer's disease, aging, depression, Parkinson's disease, Huntington's disease, stroke, and addiction, often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic-pituitary-adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.

JOURNAL/nrgr/04.03/01300535-202509000-00026/figure1/v/2024-11-05T132919Z/r/image-tiff Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease. The accumulation of amyloid-β peptides, a key hallmark of Alzheimer's disease, is believed to induce neuritic abnormalities, including reduced growth, extension, and abnormal growth cone morphology, all of which contribute to decreased connectivity. However, the precise cellular and molecular mechanisms governing this response remain unknown. In this study, we used an innovative approach to demonstrate the effect of amyloid-β on neurite dynamics in both two-dimensional and three-dimensional culture systems, in order to provide more physiologically relevant culture geometry. We utilized various methodologies, including the addition of exogenous amyloid-β peptides to the culture medium, growth substrate coating, and the utilization of human-induced pluripotent stem cell technology, to investigate the effect of endogenous amyloid-β secretion on neurite outgrowth, thus paving the way for potential future applications in personalized medicine. Additionally, we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition. We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway, achieved through modulation with Y-27632 (a ROCK inhibitor) and Ibuprofen (a Rho A inhibitor), respectively, can restore and even enhance neuronal connectivity in the presence of amyloid-β. In summary, this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition, but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-β peptides, along with potential intervention points to restore neurite growth. Thereby, we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical, predictive outcomes of drugs and their ability to promote neurite outgrowth, both generally and in a patient-specific manner.

Alzheimer's disease is a common neurodegenerative disorder in older adults. Despite its prevalence, its pathogenesis remains unclear. In addition to the most widely accepted causes, which include excessive amyloid-beta aggregation, tau hyperphosphorylation, and deficiency of the neurotransmitter acetylcholine, numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition. Dopamine is a crucial catecholaminergic neurotransmitter in the human body. Dopamine-associated treatments, such as drugs that target dopamine receptor D and dopamine analogs, can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations. However, therapeutics targeting the dopaminergic system are associated with various adverse reactions, such as addiction and exacerbation of cognitive impairment. This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease, focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs. The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease, thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

JOURNAL/nrgr/04.03/01300535-202509000-00028/figure1/v/2024-11-05T132919Z/r/image-tiff Successful polyethylene glycol fusion (PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to: (1) rapidly restore electrophysiological continuity; (2) prevent distal Wallerian Degeneration and maintain their myelin sheaths; (3) promote primarily motor, voluntary behavioral recoveries as assessed by the Sciatic Functional Index; and, (4) rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex (e.g., toe twitch) or voluntary behaviors. The preceding companion paper describes sensory terminal field reorganization following PEG-fusion repair of sciatic nerve transections or ablations; however, sensory behavioral recovery has not been explicitly explored following PEG-fusion repair. In the current study, we confirmed the success of PEG-fusion surgeries according to criteria (1-3) above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis rats. Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws. Dorsal von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve transections. Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex. Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats. Following sciatic transection, all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury. However, PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats. Furthermore, PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recovery compared with those without Sciatic Functional Index recovery, suggesting a correlation between successful PEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries. This correlation was independent of the sex or strain of the rat. Furthermore, our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths. No chronic hypersensitivity developed in any rat up to 12 weeks. All these data suggest that PEG-fusion repair of transection peripheral nerve injuries could have important clinical benefits.

Hearing loss is the third leading cause of human disability. Age-related hearing loss, one type of acquired sensorineural hearing loss, is largely responsible for this escalating global health burden. Noise-induced, ototoxic, and idiopathic sudden sensorineural are other less common types of acquired hearing loss. The etiology of these conditions is complex and multi-factorial involving an interplay of genetic and environmental factors. Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss. Short non-coding RNA sequences known as microRNAs (miRNAs) have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response. Sensory hair cell death is a central histopathological finding in sensorineural hearing loss. As these cells do not regenerate in humans, it underlies the irreversibility of human age-related hearing loss. Ovid EMBASE, Ovid MEDLINE, Web of Science Core Collection, and ClinicalTrials.gov databases over the period August 1, 2018 to July 31, 2023 were searched with "hearing loss," "hypoxamiRs," "hypoxia," "microRNAs," "ischemia," and "oxidative stress" text words for English language primary study publications or registered clinical trials. Registered clinical trials known to the senior author were also assessed. A total of 222 studies were thus identified. After excluding duplicates, editorials, retractions, secondary research studies, and non-English language articles, 39 primary studies and clinical trials underwent full-text screening. This resulted in 11 animal, in vitro , and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review. MiRNAs miR-34a and miR-29b levels increase with age in mice. These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator-1-alpha (SIRT1/PGC-1α), SIRT1/p53, and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis. Furthermore, hypoxia and oxidative stress had a similar adverse apoptotic effect, which was inhibited by resveratrol and a myocardial inhibitor-associated transcript, a miR-29b competing endogenous mRNA. Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice - an effect that was corrected by inner ear stem cell-derived exosomes. There is ongoing work seeking to determine if these findings can be effectively translated to humans.

Traumatic brain injury and Alzheimer's disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier dysfunction, neuroinflammation, and cognitive deficits. Furthermore, traumatic brain injury can exacerbate Alzheimer's disease-like pathologies, potentially leading to the development of Alzheimer's disease. Nanocarriers offer a potential solution by facilitating the delivery of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease. Unlike traditional approaches to neuroregeneration, this is a molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on the use of nanocarrier systems for the efficient and precise delivery of siRNAs, discussing the advantages, challenges, and future directions. In principle, siRNAs have the potential to target all genes and non-targetable proteins, holding significant promise for treating various diseases. Among the various therapeutic approaches currently available for neurological diseases, siRNA gene silencing can precisely "turn off" the expression of any gene at the genetic level, thus radically inhibiting disease progression; however, a significant challenge lies in delivering siRNAs across the blood-brain barrier. Nanoparticles have received increasing attention as an innovative drug delivery tool for the treatment of brain diseases. They are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier, targeted drug delivery, enhanced drug stability, and multifunctional therapy. The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach. Although this strategy is still in the preclinical exploration stage, it is expected to achieve clinical translation in the future, creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer's disease associated with traumatic brain injury.