Biochemistry [JOURNAL]
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200 papers
Structural and Functional Insights into pH-Dependent Dynamics of Pheromone-Binding Protein 3 (OfurPBP3).
Paudel P, Al Danoon O, Azeez AT … +1 more , Mohanty S
Biochemistry · 2026 Jun · PMID 42268728 · Publisher ↗
Male moths of (Asian corn borer) rely on a highly sensitive olfactory system to detect female-emitted sex pheromones essential for mating. Pheromone-binding proteins (PBPs), expressed in male antennae, transport hydroph...
Male moths of (Asian corn borer) rely on a highly sensitive olfactory system to detect female-emitted sex pheromones essential for mating. Pheromone-binding proteins (PBPs), expressed in male antennae, transport hydrophobic pheromones through the aqueous sensillar lymph to olfactory receptors. OfurPBP3, a male-biased PBP, plays a key role in species-specific pheromone detection. Here, we report the cloning, recombinant expression, refolding, purification, and structural characterization of OfurPBP3. Fluorescence binding assays revealed high nanomolar affinity for both - and -isomers of tetradec-12-en-1-yl acetate pheromone. Circular dichroism and NMR studies demonstrated that although OfurPBP3 retains a predominantly α-helical secondary structure under acidic conditions, its tertiary structure is perturbed, exhibiting increased conformational dynamics and features consistent with partial unfolding. Upon restoration to pH 6.5, the native tertiary structure is recovered, indicating that the pH-induced structural changes are reversible. Homology modeling predicted a conserved PBP fold containing a hydrophobic pocket. Molecular docking studies identified residues potentially involved in ligand recognition. The behaviors of OfurPBP3 in acidic pH are reminiscent of the molten-globule-like states previously reported for other pheromone-binding proteins from species. Collectively, these findings suggest that ligand release in PBPs is associated with pH-dependent structural destabilization and partial unfolding, rather than a canonical two-state (open ⇌ closed) conformational switch as described for several other lepidopteran PBPs, such as ApolPBP1.
Backbone Nitrogen Substitution Probes the Role of Glycine Residues at GxxxG Interfaces in Transmembrane Helices.
Thomas D, Gu F, Newberry RW
Biochemistry · 2026 Jun · PMID 42263016 · Full text
Association of transmembrane helices is central to the structure and function of membrane proteins. A common feature of these interfaces is the GxxxG motif, which allows for close contact between the protein backbones, r...
Association of transmembrane helices is central to the structure and function of membrane proteins. A common feature of these interfaces is the GxxxG motif, which allows for close contact between the protein backbones, resulting in the formation of a network of weak hydrogen bonds between C-H donors and carbonyl acceptors on opposing helices (i.e., C-H···O═C hydrogen bonds). Engineering these interfaces holds promise for the control of membrane protein activity, but few strategies exist for the substitution of the critical glycine residues, which lack mutable side chains. Herein, we replace glycine residues at the dimerization interface of single-pass transmembrane proteins (i.e., glycophorin A and BNIP3) with aza-glycine, which substitutes the α-carbon with nitrogen. We hypothesized that aza-glycine incorporation would enhance intermolecular association by introducing a stronger hydrogen-bond donor and increasing solvophobic interactions within the lipid bilayer. In contrast, FRET-based measurements of helix association showed that aza-glycine substitution was insufficient to increase dimerization affinity, which we attribute to the decreased helical propensity of aza-glycine. Our results demonstrate a synthetic strategy to probe the determinants of membrane-protein folding and inform the design of transmembrane peptidomimetics.
GPCR Biased Signaling: Opportunities and Challenges.
Roth BL
Biochemistry · 2026 Jun · PMID 42257337 · Publisher ↗
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mRNA Display for Identifying Peptide Substrates of Enzymes.
Trifonov GM, Sames EC, McAllister TE
Biochemistry · 2026 Jun · PMID 42257275 · Publisher ↗
Among display technologies, mRNA display has emerged as a powerful approach to identify ligands for proteins of interest. Applying the same methods to studying the substrates of protein/peptide-modifying enzymes has rec...
Among display technologies, mRNA display has emerged as a powerful approach to identify ligands for proteins of interest. Applying the same methods to studying the substrates of protein/peptide-modifying enzymes has received much less attention, but progress in this area has accelerated rapidly over the last 5 years. In this article, we review the published literature to date (up to December 2025) of dedicated efforts to identify and understand enzyme substrate preferences using mRNA- or cDNA-display. We include observations of trends from these reports over time and reflections on where the area may go in the future. We hope this will serve as a useful primer for researchers in this and related areas.
Versatile Sulfonium Tools for Chemoselective Modification of Proteins.
Zhao Y, Luo T, Wu M
Biochemistry · 2026 Jun · PMID 42253057 · Publisher ↗
Protein modifications are important for regulating or expanding protein functions. In eukaryotic cells, protein post-translational modifications are important mechanisms for the precise regulation of cellular activities....
Protein modifications are important for regulating or expanding protein functions. In eukaryotic cells, protein post-translational modifications are important mechanisms for the precise regulation of cellular activities. In addition, incorporation of chemical groups in laboratories enables protein tools and protein drugs for broad applications. Therefore, it is very important to develop chemical methods to prepare proteins with specific modifications. Chemoselective modification of proteins is a straightforward method using chemical reagents on proteins of interest, and the key challenge is the development of reagents with both reactivity and selectivity. Sulfonium is a unique electron-deficient group that has potential in substitution, elimination, and addition reactions. In biochemistry, -adenosyl methionine, as a natural sulfonium, demonstrates reactivity and biocompatibility. Therefore, sulfonium has potential for diverse protein modifications, and many reagents have indeed been reported. In this perspective, we summarize the research on the development of sulfonium tools for protein modifications. In early times, sulfonium was developed for cysteine- and lysine-selective modification. As the demand for site-selective modification has increased in the field, more types of sulfonium tools have been developed to target cysteine, lysine, arginine, tryptophan, and tyrosine with site precision. The sulfonium tools enable covalent drugs for cancer therapy, covalent probes for protein identification, etc. Finally, we discuss our perspective on sulfonium tool development in the future.
No Time to Fold: Intrinsically Disordered Microproteins in Action.
Chen T, Cao K, Martinez TF
Biochemistry · 2026 Jun · PMID 42247584 · Full text
Advances in genomics, proteomics, and bioinformatics have uncovered the existence of thousands of translated small open reading frames less than 100-150 codons in length that encode microproteins. In addition to their di...
Advances in genomics, proteomics, and bioinformatics have uncovered the existence of thousands of translated small open reading frames less than 100-150 codons in length that encode microproteins. In addition to their diminutive size, microproteins are also often predicted to be intrinsically disordered based on their enrichment in disordered-promoting amino acids. Microproteins have since been found to regulate diverse cellular processes, including DNA repair, mRNA decay, mitochondrial metabolism, and ribosome biogenesis, among others. While only a small fraction of microproteins have been functionally characterized, many examples have been found to act as regulators of larger proteins and protein complexes in ways similar to annotated intrinsically disordered proteins (IDPs). In this review, we summarize the functions and mechanisms of several disordered microproteins while exploring the approaches used to study their disordered nature, their regulation by post-translational modifications, and potential strategies to therapeutically target them in disease. These examples underscore how investigations of disordered microproteins deepen our understanding of how biological processes are regulated and emphasize how close collaboration between the microprotein and IDP fields can enhance these efforts.
-Palmitoylation in Health and Disease.
Wong W, Hu M, Isaacson RL
Biochemistry · 2026 Jun · PMID 42247253 · Full text
-palmitoylation is a reversible protein post-translational modification whereby a 16C fatty acid chain is attached to a cysteine residue via a thioester bond. This modification is crucial in regulating protein localizati...
-palmitoylation is a reversible protein post-translational modification whereby a 16C fatty acid chain is attached to a cysteine residue via a thioester bond. This modification is crucial in regulating protein localization, conformation, stability, and interaction with other molecules. It influences multifarious physiological functions, from immune signaling to cellular apoptosis. In recent years, protein palmitoylation and diverse disease pathogenesis have been increasingly linked; this review intends to present a recent overview of the area, covering its catalysis mechanisms, functional significance, and role in diseases while discussing research challenges to strengthen our understanding of -palmitoylation. Rather than providing an exhaustive summary, this review focuses on specific recent exemplars to illustrate the biological importance of -acylation.
Elucidation of the Pathway for the Biosynthesis of the Undecorated Capsular Polysaccharide from the HS:19 Serotype of the Human Pathogen .
Xiang DF, Narindoshvili T, Raushel FM
Biochemistry · 2026 Jun · PMID 42241030 · Full text
is the leading cause of food poisoning in the United States and Europe. The bacterium is commensal in poultry, and the ingestion of contaminated or undercooked chicken products can result in rather severe cases of nausea...
is the leading cause of food poisoning in the United States and Europe. The bacterium is commensal in poultry, and the ingestion of contaminated or undercooked chicken products can result in rather severe cases of nausea, abdominal pain, and diarrhea. Protecting the bacterium from the host immune system is a thick polysaccharide coat known as the capsular polysaccharide. The repeating disaccharide unit in the undecorated capsular polysaccharide from the HS:19 serotype of consists of N-acetyl-d-glucosamine (GlcNAc) and the serinol amide of d-glucuronic acid (GlcA). It was demonstrated that the GT2 glycosyltransferase from the N-terminal domain of HS19.08 catalyzes the transfer of d-glucuronic acid from UDP-GlcA to C3 of the GlcNAc moiety at the nonreducing end of the growing polysaccharide chain. The carboxylate of the added GlcA is then amidated by the ATP-dependent ligase activity of the C-terminal domain of HS19.11 using ()-serinol-phosphate. The phosphorylated serinol amide is subsequently dephosphorylated by the catalytic activity of HS19.09. In the final step of the series, the GT2 glycosyltransferase from the N-terminal domain of HS19.11 catalyzes the transfer of GlcNAc from UDP-GlcNAc to C4 of the amidated glucuronic acid. This series of reactions has been exploited to enzymatically synthesize and isolate defined oligomers containing 2, 3, 5, and 7 monomeric units, and procedures were developed for the synthesis of oligomeric mixtures ranging from 9 to 15 monomeric units.
Structure-Activity Relationship Study of Antimicrobial Peptide with Cross-Kingdom Activity.
Palakkurussi Rathessan A, Ghazisaeedi F, Unmesh K … +7 more , Bingül PK, Kupke J, Chowdhary S, Hanke D, Mroginski MA, Fulde M, Koksch B
Biochemistry · 2026 Jun · PMID 42240482 · Full text
The widespread emergence of antibiotic-resistant pathogens poses a significant global health challenge and underscores the need for novel approaches to accelerate antimicrobial discovery. Antimicrobial peptides (AMPs) ha...
The widespread emergence of antibiotic-resistant pathogens poses a significant global health challenge and underscores the need for novel approaches to accelerate antimicrobial discovery. Antimicrobial peptides (AMPs) have gained attention as promising candidates due to their broad-spectrum activity, including efficacy against multidrug-resistant bacterial strains. SAJO-2, an antimicrobial peptide developed by Sarojini and colleagues, features a tryptophan zipper-like motif incorporating a central d-Phe-2-Abz unit, where 2-Abz functions as a conformationally constrained β-turn-inducing peptidomimetic scaffold. Modification of SAJO-2 in prior joint work from our groups through differential fluorination enhanced its antimicrobial potency; however, it also increased susceptibility to enzymatic digestion by β-trypsin. To address this limitation, the current research focuses on improving the overall efficacy of SAJO-2 through the incorporation of D-amino acids, beta backbone modifications, and a bulky pentafluorinated amino acid residue. All modified peptides exhibit resistance to enzymatic degradation, while antimicrobial activity was retained to differing degrees across organisms.
Structural Basis for Mechanical Coupling in Hsp90: Hinge Flexibility Coordinates ATP Gate Closure and β-Strap Release.
Magnan B, LaPointe P, Spyracopoulos L
Biochemistry · 2026 Jun · PMID 42234987 · Publisher ↗
Heat shock protein 90 (Hsp90) is an essential molecular chaperone that relies on coordinated, high-energy, ATP-driven conformational rearrangements to remodel a diverse array of client proteins. A central requirement of...
Heat shock protein 90 (Hsp90) is an essential molecular chaperone that relies on coordinated, high-energy, ATP-driven conformational rearrangements to remodel a diverse array of client proteins. A central requirement of the Hsp90 catalytic cycle is the structural coupling between the ATP gate and the N-terminal β-strap. Here, we identify the C-terminal hinge of the ATP gate (G123) as a critical mechanical element mediating this coordination. Using site-specific backbone restriction, F nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we show that hinge plasticity is indispensable for the transition to the closed state and facilitates a primed gate conformation that precedes β-strap release. Restricting hinge flexibility mechanically decouples the β-strap from the ATP gate, trapping Hsp90 in a conformation that precludes chaperone closure. Furthermore, our studies of asymmetric heterodimers demonstrate that hinge rigidity dictates the direction of intersubunit activation or repression across the dimer interface. These findings reveal that the ATP gate hinge functions as a mechanical switch that governs the global conformational state of the Hsp90 complex. These results define a structural basis for Hsp90 activation and highlight how local backbone dynamics drive long-range regulation of the Hsp90 dimer.
Multidirectional Effects of SARS-CoV-2 Coronavirus Proteins on Amyloid Transformation of Alpha-Synuclein.
Stroylova YY, Konstantinova AV, Pozdyshev DV … +3 more , Katrukha IA, Yousefi R, Muronetz VI
Biochemistry (Mosc) · 2026 May · PMID 42219393 · Publisher ↗
Parkinson's disease is associated with amyloid aggregation of alpha-synuclein, which could be affected by the proteins of the SARS-CoV-2 coronavirus, possibly accelerating and provoking neurodegeneration. The purpose of...
Parkinson's disease is associated with amyloid aggregation of alpha-synuclein, which could be affected by the proteins of the SARS-CoV-2 coronavirus, possibly accelerating and provoking neurodegeneration. The purpose of this work was to compare the effects of the N-protein and the receptor binding domain (RBD) of the S protein on fibrillization of the alpha-synuclein preparation produced using an original technique that excludes presence of non-native forms of alpha-synuclein that alter kinetics of the process. Presence of an elongated form of alpha-synuclein in the previously studied protein preparations is associated with the erroneous reading of the rare for TGA stop codon in the pET33b(+) expression plasmid as tryptophan, which led to the continued translation to the next stop codon. To prevent this effect, a new plasmid design was suggested with replacement of the original stop codon with a double stop codon TAA, which made it possible to obtain a homogeneous protein preparation without the admixture of alpha-synuclein with increased molecular weight. It has been shown that the N-protein is able to accelerate alpha-synuclein fibrillization, while the RBD of the S protein inhibits aggregation. According to the electron microscopy data, structure of the fibrils formed in the presence of viral proteins is also different. The obtained data are important for understanding the mechanisms of development of post-covid synucleinopathies, as well as consequences of vaccination with the viral proteins.
Dependence of Antioxidant and Transcriptional Responses to Periodic Hypoxia on Sex and Age in Rats.
Kabiolskaya SD, Patiavina OI, Kabiolskiy IA … +5 more , Savushkina OK, Tereshkina EB, Prokhorova TA, Sebentsova EA, Levitskaya NG
Biochemistry (Mosc) · 2026 May · PMID 42219392 · Publisher ↗
Periodic hypoxia is a condition characterized by alternating episodes of oxygen deprivation (hypoxia) and periods of normal or elevated oxygen levels (reoxygenation). Depending on severity and duration of exposure, perio...
Periodic hypoxia is a condition characterized by alternating episodes of oxygen deprivation (hypoxia) and periods of normal or elevated oxygen levels (reoxygenation). Depending on severity and duration of exposure, periodic hypoxia can activate both protective and pathological mechanisms. The aim of this study was to evaluate dependence of the effects of acute and periodic hypoxia on sex and age of rats. Male and female Wistar rats aged 2 and 4 months were used. The animals were exposed to normobaric hypoxia (8% O, 2 h) either once or daily for 5 consecutive days. Subsequently, changes in body weight, activity and content of antioxidant system enzymes in blood plasma, as well as expression levels of the HIF-1α, GPx4, BDNF, and caspase-3 genes in the frontal cortex, hippocampus, and striatum of the brain were assessed. It was shown that daily hypoxia exposure leads to the decrease in body weight in both male and female rats of both ages. In the males, age-dependent changes in activity of antioxidant enzymes and increased expression of hypoxia marker genes in the brain were observed after a single hypoxia exposure. After multiple exposures, the recorded parameters did not differ from the control values. In the females, exposure to hypoxia did not affect activity of antioxidant enzymes, and increase in the expression of the studied genes was observed only after five daily exposures to hypoxia. The experiments revealed significant differences in the response to acute and periodic hypoxia exposure between male and female rats. These data should be considered when developing experimental models of periodic hypoxia and studying the mechanisms of adaptive and pathological reactions of the body to repeated hypoxia/reoxygenation episodes.
Effect of the PPARγ Agonist Pioglitazone on Rat Behavior and Expression of Epileptogenesis-Related Genes during the Latent Phase of the Lithium-Pilocarpine Model.
Kharisova AR, Zubareva OE, Kovalenko AA … +2 more , Sinyak DS, Zaitsev AV
Biochemistry (Mosc) · 2026 May · PMID 42219391 · Publisher ↗
Epilepsy is a severe chronic condition that remains pharmacoresistant in approximately 30% of the patients, which necessitates the search for new treatment approaches. Epileptogenesis involves disruption in the interacti...
Epilepsy is a severe chronic condition that remains pharmacoresistant in approximately 30% of the patients, which necessitates the search for new treatment approaches. Epileptogenesis involves disruption in the interaction between metabolic pathways and neuronal signaling. A promising therapeutic target is the peroxisome proliferator-activated receptors (PPARs), which integrate metabolic and anti-inflammatory signals. The aim of this work was to evaluate effects of the PPARγ agonist pioglitazone on the complex of epileptogenesis manifestations: behavior and expression of the genes encoding glial markers, cytokines, neurotrophic factors, and glutamate receptor subunits during the latent phase of the lithium-pilocarpine model in rats. The study was conducted with 8-week-old male Wistar rats divided into control and experimental groups. Pioglitazone was administered at low doses (7 mg/kg after status epilepticus, followed by 1 mg/kg/day for 7 days). On the days 8-9, locomotor and social activities were assessed using the Open Field and Social Interaction tests. On the day 10, expression of the genes encoding markers for activation and various states of astro- and microglia, cytokines, neurotrophic factors, and glutamate receptor subunits was analyzed in the dorsal hippocampus and temporal cortex using RT-qPCR. It was shown that pioglitazone partially alleviated the pilocarpine-induced social deficit. In the brain of rats with the epilepsy model, increased expression of the glial activation markers (, ) and cytokines (, ) was found, which was weakly affected by administration of pioglitazone. At the same time, the drug completely prevented the pilocarpine-induced decrease in the expression of the glutamate receptor subunit gene . The obtained data suggest that, at the applied doses, pioglitazone primarily modulates expression of the genes related to synaptic plasticity and does not exert a significant effect on expression of the genes associated with glial activation and inflammation. Thus, activation of PPARγ as a metabolic sensor during epileptogenesis could stabilize transcriptional programs that are important for maintaining synaptic homeostasis, which opens the possibilities for targeted modulation of metabolic pathways in epilepsy therapy.
A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy.
Burak MV, Pukaeva NE, Kryshkova VS … +8 more , Kukharskaya OA, Nazdracheva MR, Pukhov SA, Rachenkov KA, Stavrovskaya AV, Fisenko VP, Kukharsky MS, Bachurin SO
Biochemistry (Mosc) · 2026 May · PMID 42219390 · Publisher ↗
Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson's disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessit...
Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson's disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessitating the search for new therapeutic agents. One promising strategy involves the use of low-molecular-weight compounds capable of inhibiting the formation of toxic protein aggregates. This study evaluates the anti-aggregation properties of EC3222x, a conjugate of pharmacophoric fragments of amantadine and a fluorinated derivative of tetrahydro-γ-carboline. α-ynucleinopathy was modeled n the SH-SY5Y neuroblastoma cell line by transfection with a plasmid vector encoding the mutant human α-synuclein A53T protein. EC3222x at a concentration of 1 µM reduced the number of cells with α-synuclein A53T aggregates. Its efficacy was comparable to that of SynuClean-D and Buntanetap, known inhibitors of α-synuclein aggregation. Treatment with EC3222x reduced both the level of diffusely distributed intracellular α-synuclein and the formation of mature fibrillar aggregates and large aggresomes. Importantly, EC3222x did not affect the accumulation of another aggregation-prone protein, TDP-43, in a similar cellular model, indicating its specificity for α-synuclein. These findings suggest that EC3222x may represent a promising candidate for the development of therapeutic agents targeting synucleinopathies.
Immunoinflammatory Markers in Patients with Affective Disorders: Genetic Polymorphisms, Peripheral Cytokine Levels, and Expression of IL-1β, IL-13, TNF-β, and TGF-α in Peripheral Blood Mononuclear Cells.
Mikhalitskaya EV, Levchuk LA, Boiko AS … +7 more , Vyalova NM, Epimakhova EV, Paderina DZ, Roschina OV, Simutkin GG, Bokhan NA, Ivanova SA
Biochemistry (Mosc) · 2026 May · PMID 42219389 · Publisher ↗
Cytokines play a critical role in brain functioning by modulating neurotransmitter and energy metabolism, neuroplasticity, and neuronal activity. Dysregulated or excessive cytokine production can disrupt neuronal metabol...
Cytokines play a critical role in brain functioning by modulating neurotransmitter and energy metabolism, neuroplasticity, and neuronal activity. Dysregulated or excessive cytokine production can disrupt neuronal metabolic processes and contribute to brain dysfunction. Among the proposed mechanisms underlying the development and progression of affective disorders (ADs), the cytokine hypothesis emphasizes the role of inflammatory markers as key factors in the development of depressive pathologies. The aim of this study was to investigate molecular characteristics of selected immunoinflammatory markers in patients with AD. The study included 239 patients diagnosed with AD and 205 healthy controls. Polymorphic variants of the immunoinflammatory genes (, ), (), (), and () were analyzed, and cytokine levels in the blood serum and peripheral blood mononuclear cells were measured. As association was identified between the polymorphism of the gene and AD: the carriage of the allele and the genotype of this variant was associated with an increased risk of AD. Furthermore, the levels of TGF-α and IL-13 in peripheral blood mononuclear cells and the serum content of TNF-β were significantly elevated in patients with AD compared with healthy controls. These pilot findings suggest that the studied cytokines may contribute to the pathogenetic mechanisms underlying development of ADs.
Method for Individual Assessment of Human Cerebral Cortex Activity by a Combined Use of Magnetic Resonance Spectroscopy of Glutamate and BOLD Signal Method.
Korotkov AD, Myznikov AD, Krasnov IM … +3 more , Didur MD, Cherednichenko DV, Kireev MV
Biochemistry (Mosc) · 2026 May · PMID 42219388 · Publisher ↗
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 ac...
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.
Metabolic Reprogramming of Astrocytes and Microglia as a Driver and Therapeutic Target in Epileptogenesis.
Zakharova MV, Kovalenko AA, Gorgul YA … +5 more , Schwarz AP, Zubareva OE, Kharisova AR, Diespirov GP, Zaitsev AV
Biochemistry (Mosc) · 2026 May · PMID 42219387 · Publisher ↗
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...
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.
BDNF as a Mediator between Body Metabolism and Brain Function in Health and Disease: The Case of Alcohol Dependence.
Peregud DI, Gulyaeva NV
Biochemistry (Mosc) · 2026 May · PMID 42219386 · Publisher ↗
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...
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.
Hypothalamic Regulation of the Gonadal Axis and Roles of Leptin and Insulin in It.
Zorina II, Derkach KV, Shpakov AO
Biochemistry (Mosc) · 2026 May · PMID 42219385 · Publisher ↗
The hypothalamic-pituitary-gonadal (HPG, gonadal) axis is responsible for regulating reproductive functions, and its activity is regulated by numerous hormones, including leptin and insulin. Their primary targets are hyp...
The hypothalamic-pituitary-gonadal (HPG, gonadal) axis is responsible for regulating reproductive functions, and its activity is regulated by numerous hormones, including leptin and insulin. Their primary targets are hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), which regulate secretion of gonadotropins and, thus, control puberty and fertility. The key function of leptin and insulin in hypothalamus is to mediate functional relationship between the energy availability and expenditure, on the one hand, and reproduction, which is determined, in part, by the activity of GnRH neurons, on the other. The effects of leptin and insulin on the GnRH neurons are typically indirect and mediated through other hypothalamic neurons, providing more specialized, multi-level regulation of their activity. The targets of leptin and insulin are various types of kisspeptin (Kiss1)-expressing neurons, as well as neurons expressing proopiomelanocortin (POMC, a precursor of anorexigenic melanocortin peptides), and the orexigenic factors - agouti-related peptide (AgRP) and neuropeptide Y (NPY). The Kiss1- and POMC-expressing neurons positively regulate GnRH-neurons, while the AgRP/NPY neurons are primarily involved in their negative regulation. The effects of leptin and insulin on the Kiss1-, POMC-, and AgRP/NPY-neurons, and consequently on the GnRH-neurons and the HPG axis, depend on physiological state of the organism, including its metabolic status, puberty, and gender. These effects are significantly altered in obesity and type 2 diabetes mellitus, thereby contributing to etiology and pathogenesis of the associated reproductive disorders. This review focuses on the current state of knowledge on the roles of insulin- and leptin-mediated regulation of the hypothalamic HPG axis in health and disease, as well as on the unresolved issues in this area. Understanding molecular basis of this regulation opens up broad prospects for the development of new pharmacological approaches to restoring reproductive function in obesity and diabetes.
The Roles of Corticosterone, Interleukin-1β, and Their Interactions in the Development of Stress-Induced Anxiety-Like Behavior in Laboratory Rodents.
Vysotskaya AI, Shishkina GT
Biochemistry (Mosc) · 2026 May · PMID 42219384 · Publisher ↗
Psychoemotional disorders such as depression and anxiety are associated with adverse life experiences, but the precise mechanisms underlying the induction of psychopathologies, particularly anxiety, remain unclear. Among...
Psychoemotional disorders such as depression and anxiety are associated with adverse life experiences, but the precise mechanisms underlying the induction of psychopathologies, particularly anxiety, remain unclear. Among the wide range of biological alterations triggered by stressors, two systems - the hypothalamic-pituitary-adrenocortical (HPA) axis and the immune system - have been most extensively studied. Activation of the HPA axis leads to a rapid increase in glucocorticoids (cortisol in humans and corticosterone in rodents), which play a central role in coordinating adaptive stress responses. However, this increase can also lead to the development of psychopathologies. Elevated levels of peripheral and central proinflammatory cytokines have been reported in both patients with anxiety symptoms and laboratory animals. Elucidating the contribution of immune and glucocorticoid responses to stress-related behavioral outcomes is complicated by complex and bidirectional interactions between these systems. While corticosterone, consistent with the well-established immunosuppressive activity of glucocorticoids, can exert anti-inflammatory effects, elevated levels of this hormone may also promote systemic inflammation by enhancing the production of proinflammatory cytokines. Conversely, cytokines can modulate HPA axis activity, further influencing stress responses. The review summarizes experimental evidence on the roles of glucocorticoid hormones and the key proinflammatory cytokine interleukin-1β (IL-1β), as well as their interactions, in the development of stress-induced anxiety. A better understanding of these mechanisms may help clarify the pathophysiology of anxiety disorders.
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