Disease Of Nervous System Research Articles

Free-living amoebae: a journey into historical aspects and to current discoveries

Free-living amoebas (FLA) are ubiquitous protists found in the environment. They have shown exceptional resistance to environmental challenges and play significant roles in controlling microbial populations through their predatory behaviour and microbicidal activity in both soil and aquatic ecosystems environments. However, although rare, a limited group of FLA can cause serious infections in the central nervous system and other diseases, particularly in immunocompromised individuals with high mortality rates. They can also cause keratitis in otherwise healthy individuals. This review offers a comprehensive overview of freshwater naked amoebae but does not cover all aspects in detail. Its goal is to provide a historical context for our current understanding while addressing the most critical elements of FLA biology, their pathogenic potential, and their interactions with important human pathogens.

The emerging role of 12/15-lipoxygenase in ischemic stroke.

The arachidonic acid metabolic pathway is a classic inflammatory pathway. 12/15-lipoxygenase (LOX), a member of the lipoxygenase family that metabolizes arachidonic acid, has been implicated in the pathogenesis of numerous central nervous system (CNS) diseases. Ischemic stroke is a devastating disease in which the occlusion of cerebral arteries leads to a series of pathophysiological changes in brain tissue, triggering an inflammatory cascade within the brain that results in neuroinflammation. Prior research has shown that 12/15-LOX levels in the brain are elevated following stroke. In this review, we elaborate on the key pathological mechanisms that unfold following ischemic stroke, including neuroinflammation, oxidative stress, neuronal apoptosis, and blood-brain barrier disruption, and present evidence demonstrating that 12/15-LOX inhibition could be used to treat ischemic stroke through various avenues. Furthermore, we list currently available inhibitors of 12/15-LOX and the preclinical or clinical applications, offering novel insights for the early diagnosis, prognosis evaluation, and targeted therapy in neurological diseases.

Perfil epidemiológico de mortalidade de pessoas idosas longevas no município de Ribeirão Preto, SP

Abstract Objective To characterize and analyze the mortality profile of long-lived older adults in Ribeirão Preto, SP, Brazil, comparing it with the overall deaths in the year 2019. Method A cross-sectional study utilizing data derived from death certificates. The variables analyzed included sex, age, race/ethnicity", marital status, place of residence, place of death, and cause of death according to the chapters of ICD-10, grouped by the regions of the municipality (Center, East, North, West, South, and the district). Thematic maps were created using socioeconomic data from the IBGE, density maps by sex were generated, the mortality coefficient by region was calculated, as well as age at death. Results There were 1,459 deaths (33.2%) of long-lived older adults in the municipality in 2019. The most prevalent demographic was female (61.5%), with an age range between 81 and 90 years (70.5%), White race/ethnicity (90.7%), widowed (59.2%), deaths occurring in hospitals (76.3%), respiratory system diseases (36.5%), and Alzheimer’s disease as the leading nervous system disorder (98.4%). The highest mortality coefficient was observed in the Center (6.6/1,000 inhabitants). The maps indicated a higher density of deaths in the Center, East, and West Zones for males, and in the Center, South, and East Zones for females, with these regions being predominantly wealthier. The highest age at death occurred in the Center. Conclusion This was a pioneering study in the municipality utilizing geoprocessing techniques, indicating where long-lived individuals reside and relating it to the average income of the population, which can help guide health actions for the long-lived population.

Unlocking the neuroprotective potential of Ziziphora clinopodioides flavonoids in combating neurodegenerative diseases and other brain injuries.

Ziziphora clinopodioides Lam. (Z. clinopodioides) is a traditional Chinese and ethnic medicine in Xinjiang, China with various therapeutic effects. It is primarily used for conditions such as heart disease, fever with chills, palpitations, and insomnia. Flavonoids are the main medicinal components of Z. clinopodioides, Interestingly, current research has increasingly focused on its neuroprotective effects. This study provides a comprehensive overview of the potential therapeutic applications of Z. clinopodioides and its constituents in central nervous system disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and cerebral ischemia-reperfusion injury. At present, about 25 flavonoids have been isolated and identified from various organs of Z. clinopodioides, including linarin, acacetin, hyperoside, quercetin, apigenin, luteolin, chrysin, kaempferol, baicalein, rutin and others. Modern pharmacological studies have revealed that Z. clinopodioides and its constituents exhibits neuroprotective effects in vitro and in vivo, and the mechanism of action is related to anti-apoptosis, anti-inflammatory, antioxidant, autophagy, endoplasmic reticulum stress and so on. Currently, there is limited research on the extracts of Z. clinopodioides and their potential mechanisms of action in these neurological disorders. It is also important to prioritize research on biosynthetic pathways and chemical modification approaches to fully explore and improve the neuroprotective potential of Z. clinopodioides and its flavonoids and establish a strong foundation for its clinical applications.

Actl6a regulates autophagy via Sox2-dependent Atg5 and Atg7 expression to inhibit apoptosis in spinal cord injury.

Spinal cord injury (SCI) is a severe central nervous system disorder with limited treatment options. While autophagy plays a protective role in neural repair, its regulatory mechanisms in SCI remain unclear. Actin-like protein 6A (Actl6a) influences cell fate and neural development, yet its specific role in SCI repair is not well understood. This study investigates Actl6a's function in regulating autophagy and apoptosis via the transcription factor Sox2 in SCI. This study aims to determine if Actl6a promotes neural survival post-SCI by regulating autophagy-related genes Atg5 and Atg7 through Sox2. It also examines how the demethylase Fto modulates Actl6a mRNA stability via m6A methylation. In vitro experiments were conducted using primary neurons and HT-22 hippocampal cells exposed to hydrogen peroxide (H2O2)-induced oxidative stress. Actl6a expression was manipulated by knockdown or overexpression. For in vivo studies, a rat SCI model was established with AAV-Actl6a injected at the injury site to induce Actl6a overexpression. Autophagy and apoptosis markers were analyzed using immunofluorescence, Western blotting, and qPCR. Additionally, m6A dot blot and RNA immunoprecipitation (RIP) assays were performed to assess Fto's role in regulating Actl6a mRNA methylation and stability. Actl6a expression significantly decreased after SCI, resulting in increased apoptosis. Overexpressing Actl6a enhanced autophagy, reduced apoptosis, and improved neurological function in SCI models. Mechanistically, Actl6a and Sox2 collaboratively upregulated Atg5 and Atg7 expression, promoting autophagy. Fto's modulation of Actl6a mRNA stability via m6A demethylation further influenced autophagy and apoptosis. Actl6a, through interaction with Sox2, plays a critical role in modulating autophagy and reducing apoptosis in SCI, with Fto's m6A modification affecting Actl6a stability. This Fto/Actl6a/Sox2 axis is a promising therapeutic target for SCI repair.

In silico Screening of Monamine Oxidase B Inhibitors for the Treatment of Central Nervous System Disorders

Worldwide, millions of people suffer from neurological and psychiatric conditions, such as schizophrenia, depression, and neurodegenerative diseases. These conditions are often linked to hyperactivity of monoamine oxidase B (MAO-B) in the brain, and inhibiting this enzyme can reduce oxidative stress, stabilize neurotransmitter levels, and alleviate symptoms. In this context, a pharmacophoric model was created using PharmaGist with 31 hits extracted from BindingDB to enable a pharmacophoric-based search of potential MAO-B inhibitors in ZincPharmer’s chemical space, followed by the building of 10 conformers for each molecule in the software OMEGA, screening for structural and electrostatic similarity to safinamide using ROCS (Rapid overlay of chemical structures) and EON (Electrostatic similarity for lead-hopping), respectively. In addition, the molecular docking with Gold using the score function was performed to rank the ligands with the highest probabilities of affinity to MAO-B and then discriminate those with suitable physical-chemical, pharmacokinetic, and toxicological features using the tools QikProp, SwissADME, and DEREK. Four potential ligands with selective MAO-B inhibitor properties were identified, which show promise as future therapeutic agents for MAO-B-related disorders.

Lanthanide-tetrazine probes for bio-imaging and click chemistry.

The blood-brain-barrier prevents many imaging agents and therapeutics from being delivered to the brain that could fight central nervous system diseases such as Alzheimer's disease and strokes. However, techniques such as the use of stapled peptides or peptide shuttles may allow payloads through, with bioconjugation achieved via bio-orthogonal tetrazine/norbornene click chemistry. A series of lanthanide-tetrazine probes have been synthesised herein which could be utilised in bio-orthogonal click chemistry with peptide-based delivery systems to deliver MRI agents through the blood-brain-barrier. The Gd complexes show higher relaxivities than the clinical standard of Gd(DOTA) at 1.4 T and phosphorescence is observed from the Eu and Tb complexes via tetrazine sensitization, with supporting in vitro cytotoxicity and cell imaging. A bio-orthogonal click reaction between a Gd-tetrazine complex and a cyclic-RGD-norbornene conjugate was successful and the resulting clicked probe demonstrated enhanced relaxivity and could potentially act as a peptide shuttle for the Gd MRI agent.

Design, synthesis, and evaluation of the pharmacological activity of novel NMDA receptor antagonists based on the germacrone scaffold.

The NMDA receptor has long attracted researchers' attention due to its potential as a drug target and its central role in the central nervous system. The NMDA receptor is a ligand-gated and voltage-dependent ion channel widely distributed in the central nervous system. In this study, we employed a drug design strategy combining "molecular assembly" and "combinatorial chemistry." By reducing the carbonyl group of germacrone to a hydroxyl group and esterifying it with alanine and linarinic acid, we successfully obtained nine novel germacrone derivatives through two rounds of structural optimization. We evaluated the neuroprotective activity of these nine derivatives using the MTT assay. The results revealed that compound C1 exhibited particularly outstanding activity, achieving a cell protection rate of 29.63±1.56% at a concentration of 0.05μM, outperforming the positive control drug, ifenprodil. Further experiments on NMDA-induced Ca2+ influx verified that the action site of compound C1 was the NMDA receptor, and demonstrated its superior antagonistic effect on the NMDA receptor compared to germacrone and ifenprodil. Additionally, molecular docking studies and ADMET property predictions were conducted for compound C1. The results showed that compound C1 tightly bound to the active site of the NMDA receptor and possessed favorable pharmacokinetic properties. In conclusion, compound C1, characterized by a germacrone-linarinic acid structure, not only exhibits strong antagonistic effects on the NMDA receptor but also demonstrates excellent pharmacokinetic properties, indicating its potential for further development as a therapeutic drug for central nervous system diseases.

Mechanism of P-Hydroxy Benzyl Alcohol Against Cerebral Ischemia Based on Metabonomics Analysis.

Stroke is the leading cause of death and disability worldwide, with ischemic stroke accounting for the majority of these. HBA is the active ingredient in Gastrodia elata and has potential therapeutic effects on central nervous system diseases. In this study, the cell model of cerebral ischemia was replicated by the culture method of oxygen-glucose deprivation/reoxygenation, and the rat model of vascular dementia was established by the two-vessel occlusion method. Metabolomics technology was employed to analyze the metabolic changes in ischemic neurons induced by HBA, and potential therapeutic targets were verified. The protective effects of HBA on ischemic neurons and their mitochondria were examined through multiple indicators, and the related mechanisms were verified. HBA can improve post-ischemic cognitive impairment in rats, and its mechanism is related to the regulation of the choline-activated phospholipase D2/Sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator 1α pathway to improve mitochondrial function and reduce autophagic activity to maintain mitochondrial homeostasis. It is concluded that HBA has a protective effect on neuronal damage and cognitive impairment caused by cerebral ischemia by regulating key metabolites and signaling pathways, and that it provides a new molecular target for the treatment of cerebral ischemia.

Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies.

Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy. Therefore, we focused on identifying and validating a novel specific, directly binding survivin inhibitor for cancer treatment and tumor sensitization to conventional proapoptotic therapies. In this work, we conducted a structure-based high-throughput virtual screening at the survivin homodimerization domain. Asenapine Maleate (AM), an approved drug for central nervous system diseases, was identified as a direct binder of the survivin homodimerization domain and it significantly affected cell viability of lung, colon, and brain cancer cell lines. Direct interaction of AM to survivin protein was corroborated by surface plasmon resonance and a specific survivin protein decrease was observed in cancer cells, compared to other inhibitors of apoptosis proteins. Therapeutic in vivo studies showed an impairment of tumor growth in AM-treated mice. Finally, a synergistic anticancer effect was detected in vitro when combined with different conventional chemotherapies, and in vivo studies showed higher antitumor effects when combined with cisplatin. Altogether, our results identify AM as a specific direct binding inhibitor of survivin, showing anticancer properties in vitro and in vivo and sensitizing effects when combined with cisplatin, opening the possibility of repositioning this approved drug for cancer treatment.

Potential Impact of Probiotics on Human Health and Prospects in Clinical Application

This article discusses the detailed effects of probiotics and the potential uses in curing diseases. Research shows that certain living organisms can bring about the following benefits for man; they help maintain the ratio of the good bacteria in the intestines, improve the immune system, reduce allergic reactions, aid intestinal movement and digestion. On the other hand, probiotics may also help to modulate emotions, cognition, and stress by influencing the communication between the gut-brain axis and neurotransmitter. Furthermore, the identified probiotic metabolites, the short-chain fatty acids, are involved in metabolic processes within the intestine and other organs. Probiotics also have some anti-cancer, anti-disease and anti-inflammatory effects, and can suppress pathogens and inflammation by affecting immune cells. This article also discusses the link between probiotics in the intestinal and nervous system diseases and chronic diseases and their roles in future medical science and clinical practice. Most of the current research work is done on probiotics is done in vitro and animal studies and future clinical study has to be undertaken to ascertain their mechanisms and effectiveness in human beings.

The Polygenic Nature of Multiple Sclerosis: Genetic Variants, Immunological Modulation, and Environmental Connections.

Multiple Sclerosis (MS), a debilitating inflammatory disorder of the central nervous system characterized by demyelination, is significantly influenced by polygenic variations. Although the precise cause of MS remains unclear, it is believed to arise from a complex interplay of genetic and environmental factors. Recent investigations have focused on the polygenic nature of genetic alterations linked to MS risk. This review highlights the critical role of these genetic variants in shaping disease susceptibility and progression. Specific Human Leukocyte Antigen (HLA) alleles, such as HLA-DRB1*15:01, HLA-DRB50*101, HLA-DR2+, HLA-DQ6, DQA 0102, and DQB1 0602, are implicated in immune modulation, significantly increasing the risk of developing MS. Additionally, Genome-wide Association Studies (GWAS) have identified non-HLA genetic variants that contribute to MS susceptibility, including IL-2RA (rs2104286), IL-7R (rs6897932), CD40 (rs1883832 T), CD58 (rs2300747), and others, each playing a role in immune regulation and disease progression. Dysfunctions in genes regulating myelin integrity, such as MOG (Myelin Oligodendrocyte Glycoprotein), MAG (Myelin-associated Glycoprotein), and PLP1 (Proteolipid Protein 1), further drive MS pathogenesis. Moreover, viral infections, notably Epstein-Barr Virus (EBV), Human Herpesvirus 6 (HHV-6), and measles virus, may exacerbate the development of MS by triggering immune responses. Understanding the contribution of these genetic and viral factors may shed light on the complex etiology of MS. Polygenic Risk Scores (PRS) provide a valuable tool for estimating MS susceptibility based on the cumulative effect of genetic variants. However, translating these genetic insights into clinical practice requires further validation, including environmental considerations. Investigating MS polygenicity could lead to personalized therapies, enhancing diagnosis, prognosis, and treatment, ultimately improving outcomes for MS patients.

Microglia and Immune cells interactions in multiple sclerosis cognitive impairment: a postmortem study

Multiple Sclerosis (MS), a neuroinflammatory disease of the central nervous system, is one of the commonest causes of non-traumatic disability among young adults. Impaired cognition arises as an impactful symptom affecting more than 50% of the patients and with substantial impact on social, economic, and individual wellbeing. Despite the lack of therapeutic strategies, many efforts have been made to understand the mechanisms behind cognitive impairment in MS patients. Here, we aimed to investigate whether microglia-derived synaptic elimination and immune interactions are exacerbated in MS patients with impaired cognition when compared to non-demented controls (NDC) and cognitively preserved MS patients, that may clarify the role of immune cell interplay in MS cognitive deficits. Postmortem hippocampal samples were obtained from NDCs and MS patients. Sixteen MS patients were categorized based on their cognitive status: preserved cognition (MSCP) and impaired cognition (MSCI). Immunohistochemistry studies were conducted to explore the density of microglia, their role in synaptic engulfment, and their interaction with CD8+ immune cells in the context of cognitive impairment in MS. In high synaptic density hippocampal regions, MSCI patients exhibited a massive presence of microglia cells actively engulfing both excitatory and inhibitory synapses, accompanied by morphological alterations. Additionally, there was an increased expression of the complement protein C1q particularly localized at inhibitory synapses within microglia cells, suggesting a preferential engulfment of complement-tagged inhibitory synapses in MSCI patients. Furthermore, in hippocampal lesions of MSCI patients, we detected a significant infiltration of microglia and CD8 T cells that may be contributing to the smouldering MS and cognitive deterioration. These findings demonstrate that cognitive deficits occurring in MS are associated with microglia engulfment of C1q-tagged inhibitory synapses, which may be driven by direct or indirect stimulation from CD8+ T cells.

The Clinical Utility of the Ocrelizumab for the Patients with Multiple Sclerorsis

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease of the central nervous system, primarily affecting young adults, and is characterized by demyelination and neurodegeneration. Although several disease-modifying therapies (DMTs) are available in Korea, patients who experience inadequate responses or disease progression continue to require more effective and safer therapeutic options. Ocrelizumab, a humanized monoclonal antibody targeting CD20 of B cells, has shown high efficacy in both relapsing forms of multiple sclerosis and primary progressive multiple sclerosis patients. It was approved by the Food and Drug Administration in 2017 and approved by Ministry of Food and Drug Safety Korea in 2024. Clinical trials such as the OPERA and ORATORIO studies demonstrated that ocrelizumab significantly reduced relapse rates, disability progression, and magnetic resonance imaging lesions compared to interferon beta 1a or placebo. Real-world data further supports its clinical value, showing similar or superior efficacy to other high-efficacy DMTs. Long-term safety profile of ocrelizumab remains favorable, with manageable risks such as infections, particularly lower respiratory tract and urinary tract infections. This review discusses the clinical value of ocrelizumab in the treatment of multiple sclerosis, its potential as a tolerable high efficacy treatment option for patients in need of more effective therapies. Based on the clinical evidence, ocrelizumab offers a promising therapeutic opportunity for Korean MS patients, especially those with high disease activity, and is expected to become an essential part of MS treatment strategies worldwide.

Immunogenicity and safety of Vero cell culture-derived Japanese encephalitis vaccine: a phase 3 study in Chinese infants

ABSTRACT Background Japanese encephalitis (JE) is a severe infectious disease of the central nervous system. Vaccination with Vero cell culture-derived vaccines may effectively reduce JE incidence. Research Design and Methods In this single-center, randomized, blinded, positive-controlled clinical trial in China involving 600 healthy infants aged 6–11 months, participants were divided into experimental and control groups administered JEV-PI and JEV-LI, respectively. Antibody titers were determined after 0- and 7-day immunization schedules. A booster dose followed 12 months later. Results After primary vaccination and before booster vaccination, the positive conversion rate, geometric mean titer (GMT), and geometric mean increase (GMI) of JEV-PI-neutralizing antibodies exceeded those of JEV-LI. After booster immunization, the GMT and GMI of JEV-PI were higher than those of JEV-LI. After primary immunization, the local, systemic, and overall adverse reactions were of grades 1 and 2, with a low incidence of grade 3. After booster immunization, these differences were mainly grades 1 and 2, with no differences between JEV-PI and JEV-LI. Conclusion JEV-PI is a promising vaccine as infants acquired long-lasting and highly neutralizing immune antibodies after inoculation with JEV-PI. Trial Registration The trial was registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj = 203130; registration number: ChiCTR2300074692; registration date: 14/08/2023).

Summary of Cladribine (from Development to Clinical and Practical Treatment)

Multiple sclerosis (MS) is a chronic inflammatory central nervous system disorder involving autoreactive T and B cells, causing demyelination and axonal damage. Cladribine (Mavenclad<sup>®</sup>, Merck, Rahway, NJ, USA), an oral disease-modifying therapy for relapsing-remitting MS, offers a short, simplified dosing schedule. Acting on CD4+, CD8+, and CD19+ cells, it reduces disease activity and relapse rates, as demonstrated in the CLARITY study, with a 57.6% reduction in annual relapse rate. Despite concerns about lymphopenia, immune recovery occurs over time. Real-world data (GLIMPSE) confirm efficacy comparable to other therapies. Early, high-efficacy treatment is crucial, necessitating policy changes to improve patient access to diverse therapies.

Platelet-rich plasma protects hippocampal neurons and memory functions in a rat model of vascular dementia.

Platelet-rich plasma (PRP) is a promising biomaterial rich in bioactive growth factors, offering potential as a therapeutic agent for various diseases. However, its effectiveness in central nervous system disorders like vascular dementia (VaD) remains underexplored. This study investigated the potential of PRP to mitigate VaD progression in vivo. A rat model of VaD was established via bilateral common carotid artery occlusion and hypovolemia operation. Rats were randomly assigned to receive either PRP or platelet-poor plasma (PPP)-the latter being a byproduct of PRP preparation and used as a reference standard-resulting in the groups designated as 'operated group (OP)+PRP' and 'OP+PPP', respectively. PRP or PPP (500 μl) was administered intraperitoneally on the day of the operation and postoperative days 2, 4, 6, and 8. Cognitive function was assessed using the Y-maze, Barnes maze, and passive avoidance tests. On postoperative day 8, hippocampal samples were subjected to histological and semi-quantitative analyses. OP exhibited significant memory decline compared to controls, while the 'OP+PRP' group showed notable improvement. Histological analysis revealed increased neuronal loss and neuroinflammation in OP hippocampi, mitigated in 'OP+PRP'. Semi-quantitative analysis showed decreased expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) in OP, restored in 'OP+PPP' and further in 'OP+PRP'. These results highlight PRP's protective effects against VaD-induced hippocampal damage and cognitive impairment, partially attributed to BDNF/TrkB pathway upregulation.

ИЗУЧЕНИЕ ВОПРОСОВ ЛЕКАРСТВЕННЫХ РАСТЕНИЙ ПРИ САХАРНОМ ДИАБЕТЕ

Diabetes mellitus (DM) is one of the most pressing health problems in many countries. DM disrupts most types of metabolism and affects many tissues and organs to varying degrees. The development of DM leads to serious complications that cause disability and high mortality. Cardiovascular system disorders, nervous system disorders, diabetic nephropathy, skin disorders, diabetic retinopathies, musculoskeletal and immune system disorders. The cause of diabetes mellitus is considered to be insulin deficiency (type I), which occurs as a result of pathological changes in the beta cells of the pancreas. Another cause is insulin insensitivity (type II). Scientists are developing antidiabetic herbal preparations that have a pronounced effect on alloxan diabetes models. The composition of the collection includes: blueberry leaves or shoots, bean pods, rose hips, nettle leaves, plantain leaves, chamomile flowers, calendula flowers, motherwort herb, St. John's wort herb, yarrow herb, licorice root, rhizomes and roots of elecampane. Preparations with an anabolic effect have been developed from restharrow and alfalfa. Their active ingredients are phenolic compounds. Currently, foreign and domestic manufacturers offer biologically active food supplements as adjuvant treatment for diabetes. The range of herbal medicines for the treatment of diabetes is small, so expanding the range of herbal preparations that regulate carbohydrate metabolism disorders and prevent complications is an urgent area of research. In this regard, collections of several medicinal plants that implement the main areas of diabetes therapy are of interest.

The Improvement Effects of Sika Deer Antler Protein in an Alzheimer's Disease Mouse Model via the Microbe-Gut-Brain Axis.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The interplay between the intestinal microbiota and metabolites is believed to influence brain function and the pathogenesis of neurodegenerative conditions through the microbe-gut-brain axis. Sika deer antler protein possesses neuroprotective properties; however, the precise mechanism by which it improves AD remains unclear. Sika deer antler protein ameliorated AD invivo by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The metabolome of brain and intestinal tissues and the microbiota of intestinal contents were tested and analyzed according to the microbe-gut-brain theory. Sika deer antler protein increased beneficial bacterial levels and decreased harmful bacterial levels. Correlation analyses using the gut flora-metabolomics pathway ultimately revealed that sika deer antler protein modulated the brain and intestinal tract bi-directionally via the tyrosine metabolism pathway, thereby establishing a connection within the microbe-gut-brain axis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the differential metabolite targets of the DAP4 group showed that the enriched pathways mainly included PI3K/AKT, which was consistent with the findings of the pharmacodynamic mechanisms observed in invivo experiments. This suggests that antler protein may be involved in microbe-gut-brain interactions through tyrosine metabolism and may improve AD by activating the PI3K/AKT/Nrf2 signaling pathway. These findings add to our understanding of the microbe-gut-brain axis facilitated by sika deer antler protein and offer novel insights for further research on sika deer antler protein in alleviating AD.

INFLUENCE OF MINE-BLAST INJURY AND COMBAT STRESS ON THE STATE OF THE VEGETATIVE NERVOUS SYSTEM

Aim. In order to study the disorders of the autonomic nervous system as a result of mine-blast trauma and combat stress, as well as to analyze the dependence of the manifestation of these disorders on the age and duration of the injury, 62 people were examined. Materials and methods. The main group consisted of 37 servicemen with mine-blast trauma (MBT) and surgical interventions, and the control group consisted of 25 civilian men. The age of the subjects ranged from 18 to 45 years. The state of the autonomic nervous system was determined using ANS Analysis equipment and included three main parameters: resting heart rate, sympathetic nervous system parameters, and parasympathetic nervous system parameters. The significance of the difference between the groups of results was checked using the Mann-Whitney test, and the relationship between them, the age of patients and the time interval from the injury was checked using the Spearman rank correlation coefficient. Results. According to the results of the study, changes in the autonomic nervous system indices were absent in the group of civilians, while significant changes in the ANS indices in the group of servicemen with combat trauma were found for all three parameters: heart rate, sympathetic and parasympathetic autonomic nervous system indices. Also, in the group with MBT, a pronounced dissonance between the indicators of the autonomic nervous system was revealed: against the background of a significant increase in sympathetic status, a significant decrease in parasympathetic status was observed (179,0 (57,5; 309,0) vs. 13,0 (10,0; 28,0). Changes in the indicators of autonomic nervous system with combat trauma did not depend on the age of patients. Instead, there was a weak but statistically significant positive correlation between the duration of the injury and the parasympathetic nervous system: rs=0.325 (p=0.049). Therefore, the early use of a set of measures that increase the activity of the parasympathetic nervous system is logical. Conclusions. There were no changes in the autonomic nervous system parameters in the civilian group, but significant changes in the ANS parameters were found in the group of military personnel with combat trauma.