Biochemistry (Moscow)最新文献

Metabolic reprogramming of astrocytes and microglia is considered a significant component of epileptogenesis, associated with the development of neuronal network hyperexcitability, neuroinflammation, and oxidative stress. This review analyzes key mechanisms of glial dysfunction, such as the shift toward aerobic glycolysis (the Warburg effect), mitochondrial disturbances, and generation of reactive oxygen species. These processes are regulated by the Wnt/GSK3β and mTOR signaling cascades, forming a vicious cycle of energy deficit, NLRP3 inflammasome activation, and excitotoxicity. Particular attention is given to strategies for correcting glial metabolism. The greatest therapeutic interest lies in systemic approaches that correct metabolism (ketogenic diet, GLP-1 and PPAR receptor agonists) and high-precision technologies for selective modulation of glial functions (RNA therapy, nanodelivery). Targeted intervention in glial metabolism opens ways to the development of anti-epileptogenic drugs capable of modifying the disease course rather than merely alleviating the symptoms. However, translation of these approaches into clinical practice requires clarification of therapeutic windows for the intervention and development of biomarkers of glial status.

Modern magnetic resonance imaging (MRI) methods enable individualized assessment of both functional brain activity and neurochemical composition. Functional magnetic resonance imaging (fMRI) allows evaluation of brain activity at rest and during task performance, while magnetic resonance spectroscopy (MRS) provides measurements of key metabolites such as choline, N-acetylaspartate, creatine, lactate, lipids, alanine, glutamine and glutamate, GABA, and myo-inositol. These approaches are widely used in both fundamental brain research and diagnostic studies. However, existing literature lacks methods for directly comparing these individual assessments, which is essential for investigating relationships between metabolite levels and brain activity. Here, we present a method for aligning individual fMRI and MRS data. Using this approach, we demonstrated a neurophysiological phenomenon in which the functional connectivity between brain regions increases while overall functional activity decreases during task performance.

Brain-derived neurotrophic factor (BDNF) is widely recognized as a critical molecule for the survival, growth, and maintenance of neurons in both the central and peripheral nervous systems, as well as for the development of cognitive abilities and emotions. However, recent studies have shown that, in addition to its role as a universal brain “fertilizer”, BDNF acts as a metabotrophin linking neuronal signaling with systemic metabolism. BDNF serves as a key factor that integrates the body’s response to stress, physical activity, and food intake with cellular mechanisms underlying neural plasticity and normal brain function. The review presents evidence supporting BDNF as a bidirectionally metabolic “bridge”: body metabolism controls BDNF production in the brain, while brain BDNF regulates body metabolism. Disruption of this regulatory axis is associated with a broad range of neurological and somatic disorders, as well as their comorbidities. Cellular mechanisms associated with disruptions in BDNF functions are explored in detail through the example of alcohol dependence, a condition characterized by both impaired brain signaling and somatic pathologies accompanied by metabolic changes.

This review summarizes current data on potential applications of the main classes of inorganic nanoparticles in ophthalmology, as well as their advantages and limitations, and systematizes data on the most studied inorganic nanoparticles, including gold and silver nanoparticles, metal oxides (e.g., iron oxide, zinc oxide), silica, and insoluble calcium salts. Particular attention is paid to their toxicity to eye tissues and the use as carriers for encapsulation and controlled release of various biologically active substances, such as antiglaucoma drugs, antibiotics, anti-inflammatory and antitumor agents. The review examines the results of in vivo experiments using nanoparticles, demonstrating their physiological effects, capacity to increase the bioavailability of drugs, and ability to prolong their therapeutic effect.

Glaucoma is a multifaceted disease characterized by optic nerve damage and retinal ganglion cell (RGC) degeneration, leading to optic neuropathy and vision loss. Neurodegenerative processes in the retina underlie glaucoma pathogenesis. Elevated intraocular pressure (IOP) is a contributing factor in the development and progression of most types of glaucoma, making IOP reduction the standard treatment approach, while existing neuroprotective therapies remain largely ineffective. Dopaminergic system (DS) of the eye and its role in ocular pathology are insufficiently studied, yet available data suggest that DS is one of the most significant regulatory systems in the eye. It is widely represented in ocular structures and participates in regulation of visual function, circadian rhythms, blood circulation, and aqueous humor dynamics, as well as in eye development. Both IOP elevation and retinal ganglion cell neurodegeneration in glaucoma are critically influenced by an imbalance in the DS components. In the vertebrate retina, dopamine serves as the primary neurotransmitter and neuromodulator. It is also a precursor to sympathetic nervous system mediators – epinephrine and norepinephrine – expanding its role in physiological processes, including IOP regulation. This review presents recent and foundational studies on the presence of dopamine and its receptors in various ocular structures, their significance in normal eye function, mechanisms of involvement in neurodegenerative processes in glaucoma, and in IOP regulation. Based on analysis of the DS role in glaucoma pathogenesis, the prospects for developing antiglaucoma drugs for neuroprotection, IOP reduction, and combined mechanisms of action are discussed. Additionally, potential use of the analysis of DS components in the tear fluid as a non-invasive test for early diagnosis, prognosis, and therapeutic justification is considered.

The innate immunity of plants is a dynamic, multilevel system traditionally divided into pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). Despite being activated by different types of receptors localized in different cell compartments, PTI and ETI are currently considered interdependent components of a single defense system. This view suggests that, due to various positive interactions between these two pathways, the innate immunity of plants is more than the sum of PTI and ETI. Available data indicate that PTI and ETI enhance each other synergistically, increasing the concentration of signaling molecules, such as components of kinase cascades, reactive oxygen species, calcium ions, and phytohormones. This leads to the activation of defense genes, providing a local response to pathogens and the development of systemic plant resistance.

Allergic contact dermatitis (ACD) is a chronic inflammatory skin disorder the development of which is driven by allergen sensitization in peripheral lymphoid organs and local cutaneous inflammation. Lymphotoxin (LT) and its receptor LTβR are critical for lymphoid organogenesis and immune regulation in barrier tissues, but their role in ACD pathogenesis remains incompletely defined. This study aimed to delineate differential contribution of the LTβR-dependent signaling in oxazolone-induced dermatitis. We examined Lta knockout (Lta KO) mice, which lack both soluble LTα3 and membrane-bound isoforms LTα1β2/LTα2β1, and the Ltbr knockout (Ltbr KO) mice, both of which lack lymph nodes. ACD was induced by repeated oxazolone application to ear skin, with assessment of clinical severity, inflammation-associated gene expression, serum IgE levels, and immune cell composition in blood and spleen. Contrary to previous reports, the Lta KO mice developed dermatitis comparable to the wild-type (WT) mice, with elevated IgE production. In contrast, the Ltbr KO mice were substantially protected from the disease, exhibiting attenuated clinical inflammation, reduced ear swelling, and decreased Tslp expression in the lesional skin at the background of a lower proportion of circulating CD4⁺ T cells. These findings indicate that LTβR-dependent signaling is pathogenic in allergic skin inflammation, while LTα-mediated pathways are dispensable, suggesting a potential role for the other LTβR ligand, LIGHT, in ACD pathogenesis. Notably, ACD developed even in the absence of lymph nodes, highlighting the importance of local, skin-resident LTβR-dependent mechanisms in the disease development.

Dynamics of glial activity changes in the subacute and chronic stages of ischemic stroke after small focal injuries remains poorly understood due to complexity of the long-term animal monitoring and data interpretation. The aim of this study was to assess relationship between the delayed morphological changes in nervous tissue after experimental stroke and lesion parameters determined in vivo at various time points. For this purpose, photothrombotic ischemia of the cerebral cortex was induced in the C57BL/6J-Tg(Thy1-GCaMP6f)GP5.17Dkim/J mice, which express fluorescent calcium sensor protein GCaMP6f in cortical neurons. Lesion (ischemic core) size was determined using wide-field optical imaging (WFOI) through a cranial window via the GCaMP6f fluorescence at 3 min, 1 day, and 7 days post-photothrombosis. On day 19, brain sections were analyzed using Nissl staining and immunohistochemistry for microglial (Iba1) and astrocytic (GFAP) markers. It was found that the signs of neuroinflammation – changes in glial cell morphology and quantity – persist in the perifocal region even 19 days after ischemia induction, despite the small lesion volume. A significant linear relationship between microglial nuclear area and lesion size on day 7 was identified. Conversely, no significant correlation was found between the lesion sizes determined in the hyperacute phase (3 min) and acute phase (1 day) and cellular parameters (cell count, morphometric parameters). This indicates that the lesion formation in the acute phase is dynamic, and only the lesion size after its stabilization influences long-term stroke outcomes. Absence of a correlation between the delayed glial changes and ischemic core size during the hyperacute and acute phases suggests that therapeutic window for interventions modulating glial activity may extend to the later period after stroke, even with small lesion size. The results also allow us to conclude that it is not necessary to make an amendment for the initial lesion size in the studies of delayed neuroglial processes in preclinical models. In turn, the correlation between the lesion size on day 7 and microglial cell nucleus area on day 19 demonstrates that the lesion size at the end of the acute phase may be one of the prognostic factors for effectiveness of the post-stroke therapy.

Presynaptic nerve terminals contain a large number of vesicles filled with neurotransmitters, whose release ensures signal transmission from the presynaptic neuron to the postsynaptic cell. Despite their morphological homogeneity, synaptic vesicles (SVs) are functionally heterogeneous and are organized into distinct groups (pools) that differ in their ability for exocytosis and mobilization, recycling kinetics, and protein composition. In addition to the classic pools – the readily releasable pool (RRP), recycling pool, and reserve pool – other populations have been identified, including spontaneously recycling vesicles, vesicles of resting pool and superpool. Vesicles from different pools engage in different modes of exocytosis and endocytosis, and the extent of interpool mixing varies depending on the synapse type and physiological or pathological conditions. Changes in the organization of SV pools underlie multiple forms of synaptic plasticity. Furthermore, SV cycling is a target of several pharmacological agents, and its disruption plays a significant role in the pathogenesis of neurodegenerative diseases. This article is a systematic review of SV pools, their organizational features in central and peripheral synapses, and implications of changes in the structure of SV pools in synaptic plasticity, action of drugs, and development of neurological disorders.

Macrophages are a heterogeneous cell population whose functional diversity is formed during their maturation and depends on factors of the microenvironment after their migration into the bloodstream or tissues. One such factor is the pro-inflammatory protein cyclophilin A (CypA, 18 kDa). Using a model of early human monocytic THP-1 cells, it was shown that recombinant human CypA (rhCypA) exerts a differentiating effect on these cells, inducing their maturation, adhesion, and spreading. Under the effect of rhCypA, the THP-1 cells developed an actin cytoskeleton characteristic of motile cells with numerous pseudopodia and podosomes, which ensure tight adhesion of the cells to the substrate and determine their migratory capabilities. Combination of low concentrations of rhCypA and other activators (phorbol myristate acetate) showed an additive effect and ensured effective monocyte differentiation. It was shown that rhCypA, along with other pro-inflammatory factors (IFNγ, TNFα), promotes cell fusion and induces formation of multinucleated macrophages, which are formed during osteoclast maturation under normal conditions as well as during granuloma formation in chronic inflammation (tuberculosis, Crohn’s disease). Multinucleated giant cells have significantly higher functional activity (phagocytosis, bactericidal, and pro-inflammatory activity) compared to the mononuclear forms. The study showed that rhCypA enhances expression of the CD147 molecule, an integral functional regulator of CD29 and CD98 molecules involved in the processes of cell adhesion and fusion. Elevated doses of CypA cause deterioration in macrophages, inducing their apoptosis, which may play a role in regulation of the immune response. The findings of this study determined the mechanisms by which secreted CypA mediates monocyte differentiation and maturation, as well as it showed functional role of macrophages in the development of the immune response, which could facilitate further development of therapeutic approaches for the treatment of infectious, autoimmune, and other diseases.