Search Results (2,174)

The transcriptomic effects of hybridization and triploidization were investigated in diploid and triploid rainbow trout, diploid brook trout, as well as triploid hybrids of rainbow trout and brook trout. The examined fish were reared under identical conditions for about two and a half years after hatching. Expression of ten genes involved in cellular respiration (Atp5bp, Slc25a5), mitochondrial functioning (Mrpl28, Micu2), ribosome biogenesis (Rpl24, Rps24), proteasome-mediated protein turnover (Derl1, Psmc2), and protein chaperoning (Hsp90B1, Pdia4) was studied in liver and muscle tissues. Most of the analyzed genes (Atp5bp, Slc25a5, Mrpl28, Micu2, Rpl24, Rps24, Derl1, and Psmc2) displayed comparable expression levels in the liver tissue across the examined triploid hybrids and diploid parental species, with stabilization of genes that were both positively and negatively compensated in the triploid rainbow trout. In turn, significant upregulation of Slc25a5, Derl1, Rps24, and Rpl24 genes, together with downregulation of Micu2 gene, was observed in the triploid rainbow trout liver and muscle, respectively. On the other hand, triploid hybrids showed marked transcriptional upregulation of genes primarily associated with energy metabolism and protein synthesis (Atp5pb, Slc25a5, Rpl24, Rps24, and Pdia4) relative to all the fish groups examined. Although protein-synthesis- and energy-related genes were upregulated in the muscles of triploid hybrids, the recorded growth performance data did not indicate clear evidence of growth heterosis (MPH = −14.3% for body weight; MPH = −0.4% for body length), suggesting that potential benefits of increased heterozygosity in this cross may not be fully reflected in enhanced growth. Three- to four-fold downregulation of the heat shock protein (Hsp90B1) gene was also observed in both tissues of triploid hybrids compared with purebred diploid and triploid trout, which may reflect potential maladaptive genomic effects commonly observed in distant salmonid crosses, suggesting altered stress-response regulation in the examined triploid hybrids. Full article

Plant viruses can cause substantial yield losses, yet disease severity often varies between seasons because plants frequently experience heat or cold episodes before infection. In this study, we tested whether such temperature conditions affect the plant’s redox balance and alter its response to Tomato bushy stunt virus (TBSV) infection in Nicotiana benthamiana. Plants were exposed to short-term heat and cold stress, after which they recovered before virus inoculation. Following this, we assessed the reactive oxygen species (ROS) content, lipid peroxidation (LPO), oxidative DNA damage, stress-related proteins, redox-associated enzymes, and antioxidant metabolites. TBSV led to non-parallel ROS responses during infection, with consistently elevated hydrogen peroxide in infected plants but reduced superoxide relative to corresponding mock controls. Heat pre-exposure caused pronounced LPO that decreased further after infection, whereas cold pre-exposure stabilized malondialdehyde near levels observed at 25 °C. Both thermal stress and infection increased 8-oxo-dG and were associated with distinct changes in 8-oxoguanine glycosylase abundance. Infection strongly induced heat shock protein 90 (and moderately heat shock protein 70), while prior heat limited further chaperone induction by TBSV. These results indicate that viral infection develops within and is limited by the host’s oxidative state, where redox homeostasis may restrict infection-related processes, and infection leads to changes in this redox environment that are favorable for its development. Full article

Background: Gaucher disease (GD) is a lysosomal storage disorder caused by deficiency of β-glucocerebrosidase, leading to accumulation of glucocerebroside in lysosomes. Type 1 GD is most commonly associated with the N370S mutation and lacks neurological involvement, whereas the neuronopathic forms (types 2 and 3), frequently linked to L444P homozygosity, present with progressive neurological symptoms. Enzyme replacement therapy (ERT) effectively treats visceral manifestations but does not cross the blood–brain barrier and, therefore, does not improve neurological outcomes. Ambroxol, a plant-derived mucolytic agent, has been shown to act as a pharmacological chaperone capable of increasing residual enzyme activity and crossing into the central nervous system, with reports suggesting neurological benefit in L444P homozygotes. Methods: We evaluated 13 patients with type 3 GD (L444P/L444P homozygotes) who received ambroxol at 10 mg/kg/day for one year as part of a clinical trial. All participants had been on long-term ERT with stable biomarker levels (chitotriosidase, glucosylsphingosine [Lyso-GL1]) and hematological parameters. Neurological symptoms were assessed using the modified Severity Scoring Tool (mSST). Biomarkers and hematologic indices were monitored throughout the study. Results: Ambroxol treatment resulted in a reduction in severity or complete resolution of selected neurological symptoms in several patients. Conclusions: In patients with type 3 GD receiving stable ERT, ambroxol demonstrated beneficial effects on neurological symptom expression. Some improvement was observed in biomarkers; the activity of chitotrosidase and concentration of lyso-Gl1 decreased. These findings support the therapeutic potential of ambroxol as an adjunctive treatment for neuronopathic Gaucher disease. Full article

Autophagy is increasingly recognized as a context-dependent regulatory process that links cellular quality control with systemic metabolic and neurological homeostasis. However, how distinct autophagy pathways contribute to disease progression, and how they are dynamically modulated by host–microbiota interactions, remain incompletely understood. In this review, we synthesize recent advances in the molecular regulation of macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), with a particular emphasis on selective autophagy and its disease-specific functions. We examine emerging evidence implicating autophagy as a bidirectional modulator in neurodegenerative and metabolic disorders, highlighting conditions under which autophagy exerts protective versus maladaptive effects. Importantly, we integrate recent findings on the microbiota–gut–brain axis to illustrate how microbial signals reshape autophagic responses and influence disease susceptibility and progression. Finally, we summarize current progress and limitations in autophagy-targeted therapeutic strategies, including nanomedicine-based delivery systems, and propose conceptual frameworks to guide the development of precise, context-aware autophagy interventions. This review provides an updated and integrative perspective that bridges molecular mechanisms, host–microbiota crosstalk, and translational opportunities in autophagy-related diseases. Full article

Autophagy is a critical cellular mechanism that regulates the degradation of misfolded and aggregated proteins and non-functional intracellular organelles. Based on the fundamental qualities of the substrates targeted for degradation and the distinct molecular mechanisms involved, autophagy can be classified into three major types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Sequestosome 1 (SQSTM1)/p62, which functions as a signaling hub integrating nuclear factor kappa B (NF-κB), the mechanistic target of rapamycin complex 1 (mTORC1), and Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (NRF2) pathways, serves as a selective macroautophagy/autophagy receptor that binds ubiquitinated cargo proteins and recruits them to the autophagosome for subsequent degradation in the autolysosome. Furthermore, the phase separation of p62 is an important regulatory process in the autophagy mechanism, but recent studies have demonstrated that impaired or excessive autophagy mediated by p62 is associated with cancer development. This review summarizes the role of autophagy—including its types, mechanisms, and the pathway related to the ubiquitin-dependent selective autophagy receptor p62—in cancer progression. Full article

Chromatin is a dynamic cellular structure basically constituted by nucleosomes, which consist of a DNA sequence wrapped around an octameric histones core. Histone synthesis and transport, nucleosome formation and proper chromatin assembly is an ordered and stepwise process guided by histone chaperones. Several families of histone chaperones have been identified and one of them is the nucleosome assembly protein (NAP) superfamily. Members of this family have been involved not only in chromatin constitution and regulation but also in several other cellular processes, such as nucleocytoplasmic shuttling, DNA replication, transcription and cell-cycle regulation. Testis specific protein Y-like 2 (TSPYL2) is a peculiar member of the NAP superfamily of histone chaperone. This protein has been initially isolated as a nuclear antigen in patients affected by discoid lupus erythematosus and as a TGF-β target. Its ability to bind histones has been demonstrated. In addition, TSPYL2 has been reported to regulate transcription, cell-cycle progression and the DNA-damage response, independently of its role in chromatin organization. In accordance with its multiple functions, defects in TSPYL2 have been associated with different diseases, mainly cancer and neurodevelopmental abnormalities. In this review we summarize and discuss the multiple cellular functions of TSPYL2, pointing out new and unexpected aspects like a sex-related activity and their relationship with different diseases. Full article

Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and its derivative lyso-Gb3 within lysosomes. Beyond substrate storage, FD involves a complex interplay of molecular, metabolic, and inflammatory disturbances that collectively drive multisystemic damage. It seems that Gb3 accumulation impairs autophagic flux, promotes mitochondrial dysfunction, and triggers endoplasmic reticulum stress, leading to oxidative imbalance and bioenergetic failure. Concurrently, activation of innate immune pathways, particularly the TLR4/NF-κB axis, induces pro-inflammatory cytokine release and endothelial dysfunction, while complement activation and adaptive immune responses contribute to chronic inflammation and fibrosis. These mechanisms define a sustained state of “metaflammation,” linking lysosomal dysfunction to systemic inflammation. Understanding this molecular cross-talk provides a rationale for identifying novel biomarkers and designing therapies that go beyond enzymatic correction, including chaperone therapy, substrate reduction, and gene-based or anti-inflammatory approaches. A deeper comprehension of these interconnected patterns may guide the development of precision medicine strategies aimed at improving long-term outcomes in Fabry disease. Full article

The bacterium Yersinia enterocolitica serotype O:3 is targeted by two distinct agents, the bacteriophage φR1-37 and the bacteriocin-like enterocoliticin (a tailocin), which both utilize the lipopolysaccharide (LPS) outer core (OC) hexasaccharide as their primary host receptor. In order to understand this convergent recognition mechanism, we first characterized the enterocoliticin system, reporting the complete sequence of its large, biosynthetic gene cluster. Most of the 42 predicted gene products were functionally annotated by homology to known gene products. We then focused on identifying the receptor-binding proteins (RBPs) responsible for host attachment of both agents in order to elucidate a possible shared mechanism of binding. For phage φR1-37, the receptor binding complex was identified as the inseparable Gp298 tail fiber protein and its Gp297 trimerization chaperone, confirming its function as the RBP. Based on sequence identity with Gp298, the Orf39 gene product of the enterocoliticin cluster was predicted to be its corresponding RBP. An analytical comparison of the predicted RBPs revealed a highly conserved homologous region spanning 80–85 amino acid residues, which presents the only structural explanation for their identical receptor specificity. To resolve the binding mechanism, we generated high-confidence trimeric structural models for the Gp298 and Orf39 proteins using AlphaFold3-multimer. These models validated the high structural similarity of the RBP domains, despite global dissimilarity of the complete trimeric structures. Further docking simulations with a pentasaccharide ligand (generated by CarbBuilder) provided suggestive molecular models for the protein-carbohydrate interactions within the OC region. Intriguingly, a database search using the identified binding site motif revealed their wide and diverse presence in various phage tail proteins, suggesting that this motif is a specialized, common structure for carbohydrate recognition. This work identifies a conserved, novel sugar-binding motif as the molecular basis of host recognition for these key anti-Yersinia biologics. Full article

Clusterin is a chaperon protein that is involved in many physiological processes, including binding to beta-amyloid (Aβ). Recently, we showed that in Alzheimer’s disease (AD) model mice and human postmortem brains, there are elevated levels of methionine-oxidized clusterin in the disease state versus controls. These observations prompted us to investigate the possibility that elevated methionine-oxidized levels of clusterin in human blood plasma correlate with clinical diagnosis of both mild cognitive impairment (MCI) and AD stages. To achieve this goal, we have used a combination of Elisa kits for determining the total level of clusterin and methionine-oxidized clusterin in human blood plasma, enabling the quantification of a methionine-oxidized clusterin to total clusterin ratio. This ratio was correlated with the diagnostics of three groups of patients (normal controls (NL), MCI, and AD; with n = 44 per group). Accordingly, it was determined that there was a significant increase in the relative methionine-oxidized clusterin level in the MCI and AD groups compared to the controls. In conclusion, it is suggested that increased levels of methionine-oxidized clusterin in human blood plasma may serve as a potential marker for MCI and AD diagnosis. Full article

The silkworm, Bombyx mori, is a model organism with significant agricultural and economic importance, but it is threatened by Bombyx mori nucleopolyhedrovirus (BmNPV). A crucial chaperone, heat shock protein 90 (HSP90), can also facilitate the proliferation of viruses, and our previous quantitative acetylome analysis revealed that lysines 550 and 567 in the carboxyl-terminal domain (CTD) of Bombyx mori HSP90 (BmHSP90) were significantly deacetylated following BmNPV infection, but the underlying mechanism remained unknown. In this study, deacetylation-mimetic (K to R) mutants of BmHSP90 exhibited increased dimerization and chaperone activity compared with the wild-type. In addition, the mutants also exhibited higher affinity for actin, promoting F-actin polymerization. Collectively, these changes facilitated BmNPV replication and progeny virion production. This study reveals that the deacetylation of BmHSP90 at K550 and K567 mediates crucial host–virus interactions, providing novel insights into potential antiviral strategies. Full article

Betaines are natural nitrogen-containing compounds widely distributed in plant-derived foods and animal tissues, where they function primarily as osmolytes, chaperons, and methyl donors. As such, they have attracted increasing interest as dietary components and metabolic biomarkers in human nutrition. This study provides a comparative characterization of glycine betaine (GlyBet) and proline betaine (ProBet) by combining targeted LC–MS quantification in a representative selection of plant-based foods with complementary in silico analyses and integration of dietary intake estimates derived from published nutritional and metabolomic studies, together with human metabolomic data. A validated HPLC–ESI–MS method was applied to quantify GlyBet and ProBet across cereals, pseudocereals, vegetables, and fruits. GlyBet was found to be predominantly abundant in leafy vegetables and in several cereal and pseudocereal flours, whereas ProBet was highly enriched in citrus fruits, particularly bergamot, chinotto, and bitter orange. In silico ADMET predictions were used to provide a qualitative and comparative description of the pharmacokinetic and safety-related properties of the two betaines, indicating broadly similar hydrophilic profiles with modest differences in solubility, clearance, and predicted skin sensitization. Similarity-based target prediction analyses, used in an exploratory framework, suggest distinct contextual tendencies for the two betaines. GlyBet is primarily associated with pathways related to one-carbon metabolism and cellular stress responses, whereas ProBet shows a closer contextual association with signaling-related processes. By integrating experimental data, computational analyses, and human metabolomic information, this work supports the interpretation of betaines as biomarkers of dietary intake and systemic metabolic status. Full article

The escalating consumption of red meat is a potent environmental risk factor for inflammatory bowel disease (IBD), which is characterized by compromised expression of the xenobiotic transporter P-glycoprotein (MDR1/ABCB1). While gut microbiota metabolize dietary tryptophan into diverse indole derivatives that function as aryl hydrocarbon receptor (AhR) ligands, their differential regulation of MDR1 remains an unresolved AhR paradox. Here, we investigated the mechanisms by which two distinct metabolites, indole-3-acetic acid (IAA) and skatole, regulate MDR1 expression in human colonic epithelial Caco-2 cells. We observed that IAA selectively enhances MDR1 protein stability via an AhR-dependent pathway without inducing de novo transcription, suggesting a mechanism we term enhanced proteostasis mediated by the AhR-Hsp90 complex. Conversely, skatole, a toxic dysbiotic metabolite linked to red meat intake, triggered a time-dependent depletion of MDR1 and potently abrogated the protective efficacy of IAA. Our findings are consistent with a model in which skatole acts as a putative structural disruptor, potentially destabilizing the chaperone complex essential for MDR1 integrity. This destruction is facilitated by a key bacterial enzyme, indoleacetate decarboxylase (IAD), which is a pH-dependent metabolic switch in the gut. The modern Western diet, characterized by high protein and low fiber content, elevates colonic pH, thereby activating IAD to convert protective IAA into toxic skatole. These findings provide a molecular framework for the red meat–microbiome–barrier failure axis and highlight the restoration of the IAA/skatole balance through dietary intervention as a promising therapeutic strategy. Full article

The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic–NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer’s disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB. Full article

Small heat shock proteins (HSP20s) are known to function as molecular chaperones that bind to denatured proteins under high-temperature stress and assist in their conformational recovery, thereby contributing to plant thermotolerance. In the present study, three HSP20 genes—PcHSP12.8, PcHSP12.9, and PcHSP13.4—were identified in the transcriptome of Polygonatum cyrtonema Hua. Bioinformatics analysis indicated their phylogenetic relationships, conserved domains, and potential tertiary structures. RT-qPCR analysis revealed up-regulation of all three genes in response to heat stress. Subcellular localization studies further suggested that PcHSP12.8, PcHSP12.9, and PcHSP13.4 are predominantly localized in the nucleus. Heterologous expression of these genes in a heat-sensitive yeast mutant appeared to improve cell survival under heat stress relative to the control strain. In Arabidopsis thaliana overexpressing these genes, moderate improvements in germination rate, root elongation, and stress survival were observed compared to wild-type plants under heat stress. Transgenic lines also showed a tendency toward reduced reactive oxygen species accumulation, as reflected by decreased 3,3′-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining, together with increased activities of catalase (CAT) and peroxidase (POD), as well as higher chlorophyll retention under thermal stress. Taken together, these findings imply that the three PcHSP20 genes could be involved in thermotolerance in P. cyrtonema. Full article

With the aim of identifying key proteins that play a role in the disorder tinnitus, interactions between proteins involved in thalamo-amygdala signaling under conditions of normal hearing (NH), acoustic stimulation (AS), and tinnitus (Tin) were studied. Three gene lists compiled from the GeneCards database using keywords were characterized by analyses of overlap, protein–protein interaction (PPI) networks, and by protein-enrichment analysis. Key proteins were selected on the basis of the degree and combined score value of the corresponding PPI network. In the NH process, BDNF, CASP3, and PVALB were identified as high-degree proteins (HDPs). In the AS process, BDNF, PVALB, and DLG4 are the top three HDPs; in the Tin process, these are BDNF, APP, and TNF. In the Tin process, key proteins appear that differ pre- and postsynaptically from those detectable in NH or AS. The glucocorticoid receptor NR3C1 and its interaction with FKBP5, a glucocorticoid receptor-induced co-chaperone, appear to be of particular importance for the emotional aspects of tinnitus. In tinnitus, the HDPs, together with their high-score interaction proteins, indicate processes of chronic neurodegeneration and of changes in transcription, intercellular communication, and in the survival and growth of neurons. Full article