Biology subjects

Andreev, I.

Publications and source records attributed to Andreev, I..

5 recordsLinked to original sources

bioRxiv2026

Oleic acid suppresses NLRP3 inflammasome activation to prevent dermal macrophage death and limit imiquimod-induced psoriasis

Psoriasis is associated with altered lipid metabolism, including reduced expression of fatty acid metabolism genes and decreased circulating oleic acid. Here we report that oral oleic acid supplementation normalized serum oleic acid levels and protected from skin thickening and epidermal hyperplasia in a imiquimod mice model of psoriasis. These effects were associated with preserved skin-resident macrophage numbers and reduced expression of key psoriasis-associated inflammatory markers. Mechanistically, imiquimod induces dermal macrophage death via NLRP3/caspase-1 inflammasome activation, while adoptive transfer of dermal macrophages attenuates psoriasiform inflammation. Oleic acid rescued macrophages from imiquimod and nigericin-induced death in vitro by suppressing NF-{kappa}B and NLRP3/caspase-1 signaling, lowering IL-1{beta} and reactive oxygen species production, and restoring mitochondrial homeostasis, independently of TLR7. Together, our results position dermal macrophage survival as a previously unrecognized checkpoint in psoriasiform inflammation, and suggest that restoring lipid metabolic fitness, rather than solely targeting downstream inflammatory mediators, may offer an additional mechanism-based strategy to limit tissue- damaging inflammation.

immunology↗

bioRxiv2025

Neuroprotective action of agonists and modulators of A 1 adenosine receptors upon hyperexcitation: mechanism of the antiepileptic activity and role of neuron-glial interaction

Hyperexcitation of neuronal networks is believed to be the main reason for the excitotoxic death of neurons in different central nervous system pathologies, including epilepsy, ischemic stroke, and traumatic brain injury. Gi-coupled receptors can be considered as promising targets for the development of new neuroprotectors. Here, we studied the anticonvulsant activity of the agonists and positive allosteric modulators (PAM) of A1 adenosine receptors (A1Rs). Our experiments demonstrate that A1R agonists, CCPA and N6-cyclohexyladenosine (N6-CHA), suppress hyperexcitation in three different in vitro models, including acute glutamate excitotoxicity, NH4Cl- and bicuculline-induced epileptiform activity. We have found that the inhibitory action of the agonists is mediated by the activation of not only the neuronal A1Rs but also the astrocytic receptors. In astrocytes, A1R agonists enhance GABA release, possibly via induction of calcium transients. Using inhibitory analysis, we have demonstrated that G{beta}{gamma}-mediated activation of phospholipase C and subsequent Ca2+ mobilization from internal stores are essential for generating calcium transients in astrocytes following N6-CHA application. We have shown first that Ca2+-dependent activation of protein kinase C, which is involved in the mechanism of GABA release by astrocytes, is a pivotal step in the realization of the antiepileptic action of A1R agonists. Moreover, using the model of epileptiform activity induced by GABAAR blockade, we have shown that PAMs, PD81723 and VCP171, also suppress hyperexcitation. Furthermore, using the picrotoxin-induced epilepsy model in mice, we demonstrated that A1R agonists exhibit significant anticonvulsant effects and improve animal survival. The PAMs PD81723 and VCP171, when administered one hour before seizure induction, did not significantly affect seizure severity or survival rates. However, chronic administration of VCP171 produced a pronounced anticonvulsant effect and significantly increased survival.. Importantly, PAMs provided therapeutic benefits without significantly affecting overall activity levels in mice. Thus, our study demonstrates that both agonists and PAMs of A1R can be considered as potential therapeutic agents with antiepileptic and neuroprotective activity.

neuroscience↗

bioRxiv2024

Killer Toxin K28 resistance in yeast relies on COG complex mediated trafficking of the defence factor Ktd1

A/B toxins are a diverse family of protein toxins that enter host cells via endocytosis and induce cell death. In yeast, the A/B toxin K28 is internalised to endosomes of susceptible yeast, before following the retrograde trafficking pathway and ultimately triggering cell cycle arrest. The endolysosomal defence factor Ktd1 protects against K28, but its regulation remains unclear. Cog7, a subunit of the conserved oligomeric Golgi (COG) tethering complex, has been implicated in K28 defence, though the mechanism is unknown. We developed a high throughput K28 sensitivity assay and bespoke analysis package to show that all lobe B COG subunits (Cog5 - 8) are required for K28 resistance. Although the COG complex modulates glycosylation of the surface molecules required to bind extracellular K28, our experiments reveal that the hypersensitivity of cog mutants is primarily explained by defects in Ktd1 trafficking. Ktd1 mis-localisation in cog mutants is reminiscent to disruptions in Snc1, a surface cargo that recycles multiple times via the Golgi. This work suggests not only that the COG complex is responsible for the precise trafficking Ktd1 required to mediate toxin defence, but that Ktd1 may survey endolysosomal compartments for internalised K28. This work underpins the importance of Ktd1 in defence against the A/B toxin K28, and implies various membrane trafficking regulators might influence toxin effects in other eukaryotic systems.

cell biology↗

bioRxiv2022

Long-read genomes reveal pangenomic variation underlying yeast phenotypic diversity

Understanding the genetic causes of trait variation is a primary goal of genetic research. One way that individuals can vary genetically is through the existence of variable pangenomic genes - genes that are only present in some individuals in a population. The presence or absence of entire genes could have large effects on trait variation. However, variable pangenomic genes can be missed in standard genotyping workflows, due to reliance on aligning short-read sequencing to reference genomes. A popular method for studying the genetic basis of trait variation is linkage mapping, which identifies quantitative trait loci (QTLs), regions of the genome that harbor causative genetic variants. Large-scale linkage mapping in the budding yeast Saccharomyces cerevisiae has found thousands of QTLs affecting myriad yeast phenotypes. To enable the resolution of QTLs caused by variable pangenomic genes, we used long-read sequencing to generate highly complete de novo assemblies of 16 diverse yeast isolates. With these assemblies we resolved growth QTLs to specific genes that are absent from the reference genome but present in the broader yeast population at appreciable frequency. Copies of genes also recombine onto chromosomes where they are absent in the reference genome, and we found that these copies generate additional QTLs whose resolution requires pangenome characterization. Our findings demonstrate the power of long-read sequencing to identify the genetic basis of trait variation.

genomics↗

bioRxiv2021

KTD1 is a yeast defense factor against K28 killer toxin

Secreted protein toxins are widely used weapons in conflicts between organisms. Killer yeast produce killer toxins that inhibit the growth of nearby sensitive yeast. We investigated variation in resistance to the killer toxin K28 across diverse natural isolates of the Saccharomyces cerevisiae population and discovered a novel defense factor, which we named KTD1, that is an important determinant of K28 toxin resistance. KTD1 is a member of the DUP240 gene family of unknown function. We uncovered a putative role of DUP240 proteins in killer toxin defense and identified a region that is undergoing rapid evolution and is critical to KTD1s protective ability. Our findings implicate KTD1 as a key factor in the defense against killer toxin K28.

genetics↗