Search Results (401)

Plant pathogenic bacteria are responsible for a substantial number of plant diseases worldwide, resulting in significant economic losses. Bacteria are exposed to numerous stress factors during their epiphytic life and within the host. Their ability to survive in the host and cause symptomatic infections depends on their capacity to overcome stressors. Bacteria have evolved a range of defensive and adaptive mechanisms to thrive under varying environmental conditions. One such mechanism involves the induction of chaperone proteins that belong to the heat shock protein (Hsp) family. Together with proteases, these proteins are integral components of the protein quality control system (PQCS), which is essential for maintaining cellular proteostasis. However, knowledge of their action is considerably less extensive than that of human and animal pathogens. This study discusses the modulation of Hsp levels by phytopathogenic bacteria in response to stress conditions, including elevated temperature, oxidative stress, changes in pH or osmolarity of the environment, and variable host conditions during infection. All these factors influence bacterial virulence. Finally, the secretion of GroEL and DnaK proteins outside the bacterial cell is considered a potentially important virulence trait. Full article

Salt stress poses a significant constraint on rice production, so further exploration is imperative to elucidate the intricate molecular mechanisms governing salt tolerance in rice. By manipulating the rhizosphere microbial communities or targeting specific microbial functions, it is possible to enhance salt tolerance in crops, improving crop yields and food security in saline environments. In this study, we conducted rice rhizospheric microbial amplicon sequencing and metatranscriptome analysis, revealing substantial microbiomic differences between the salt-tolerant rice cultivar TLJIAN and the salt-sensitive HUAJING. Fungal taxa including Hormiactis, Emericellopsis, Ceriosporopsis, Dirkmeia, and Moesziomyces predominated in the rhizosphere of salt-tolerant rice, while bacterial genera such as Desulfoprunum and Hydrogenophaga exhibited notable differences. Metatranscriptomic analysis identified 7192 differentially expressed genes (DEGs) in the two rice varieties, with 3934 genes being upregulated and 3258 genes being downregulated. Enrichment analyses in KEGG and GO pathways highlighted the majority of DEGs were associated with the “two-component system”, “sulfur metabolism”, and “microbial metabolism in diverse environments”. The interaction network of DEGs and microbial taxa revealed upregulation of transporters, transcriptional factors, and chaperones, such as ABC transporters and chaperonin GroEL, in the rhizosphere microbiomes of salt-tolerant varieties. Our multi-omics network analysis unveiled that fungi like Ceriosporopsis and Dirkmeria, along with bacteria such as Desulfoprunum, Rippkaea, and Bellilinea, showed a positive correlation with flavonoid synthesis in salt-tolerant rice. This study provides an in-depth exploration of the distinctive microbial communities associated with the rhizosphere of salt-tolerant rice varieties, shedding light on the complex interactions between these microbial consortia and their host plants under stress conditions. Full article

Chaperone-mediated autophagy (CMA) is a selective autophagic pathway responsible for degrading cytoplasmic proteins within lysosomes. Monitoring CMA flux is essential for understanding its functions and molecular mechanisms but remains technically complex and challenging. In this study, we developed a pH-resistant probe, KFERQ-Gamillus, by screening various green fluorescent proteins. This probe is activated under conditions known to induce CMA, such as serum starvation, and relies on LAMP2A and the KFERQ motif for lysosomal localization and degradation, demonstrating its specificity for the CMA pathway. It enables the detection of CMA activity in living cells through both microscopy and image-based flow cytometry. Additionally, we created a dual-reporter system, KFERQ-Gamillus-Halo, by integrating KFERQ-Gamillus with the Halo-tag system. This probe not only distinguishes between protein synthesis and degradation but also facilitates the detection of intracellular CMA flux via immunoblotting and the rapid assessment of CMA activity using flow cytometry. Together, the KFERQ-Gamillus-Halo probe provides quantitative and time-resolved monitoring for CMA activity and flux in living cells. This tool holds promising potential for high-throughput screening and biomedical research related to CMA. Full article

Mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson’s disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring GBA1 mutations. Among these, compound 3 emerged as a lead candidate, demonstrating the ability to enhance GCase protein levels and enzymatic activity while effectively reducing the accumulation of toxic substrates in neuronal models. Importantly, pharmacokinetic studies revealed that compound 3 has favorable brain penetration, indicating its potential as a disease-modifying therapy for GBA1-related disorders affecting the central nervous system. This research not only offers a framework for developing allosteric GCase modulators but also unveils promising new therapeutic strategies for managing Gaucher disease and Parkinson’s disease. The ability of compound 3 to cross the blood-brain barrier emphasizes its potential significance in addressing neurological symptoms associated with these conditions. Full article

Heterologous protein expression often faces significant challenges, particularly when the target protein has posttranslational modifications, is toxic, or is prone to misfolding. These issues can result in low expression levels, aggregation, or even cell death. Such problems are exemplified by the expression of phospholipase p37, a critical target for chemotherapeutic drugs against pathogenic human orthopoxviruses, including monkeypox and smallpox viruses. The complex structure and broad enzymatic activity of phospholipase p37 render it toxic to host cells, necessitating specialized strategies for heterologous expression. In our study, we addressed these challenges using the vaccinia virus F13 protein as a model. We demonstrated that p37 can be effectively synthesized in E. coli as a GST fusion protein by co-expressing it with the GroEL/ES chaperone system and Trigger Factor chaperone. Full article

The receptor transporter protein 4 (RTP4) is a receptor chaperone protein that targets class A G-protein coupled receptor (GPCR)s. Recently, it has been found to play a role in peripheral inflammatory regulation, as one of the interferon-stimulated genes (ISGs). However, the detailed role of RTP4 in response to inflammatory stress in the central nervous system has not yet been fully understood. While we have previously examined the role of RTP4 in the brain, particularly in neuronal cells, this study focuses on its role in microglial cells, immunoreactive cells in the brain that are involved in inflammation. For this, we examined the changes in the RTP4 levels in the microglial cells after exposure to inflammatory stress. We found that lipopolysaccharide (LPS) treatment (0.1~1 µg/mL, 24 h) significantly upregulated the RTP4 mRNA levels in the microglial cell line, SIM-A9. Furthermore, the interferon (IFN)-β mRNA levels and extracellular levels of IFN-β were also increased by LPS treatment. This upregulation was reversed by treatment with neutralizing antibodies targeting either the interferon receptor (IFNR) or toll-like receptor 4 (TLR4), and with a TLR4 selective inhibitor, or a Janus kinase (JAK) inhibitor. On the other hand, the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, significantly enhanced the increase in RTP4 mRNA following LPS treatment, whereas the PKC inhibitor, calphostin C, had no effect. These findings suggest that in microglial cells, LPS-induced inflammatory stress activates TLR4, leading to the production of type I IFN, the activation of IFN receptor and JAK, and finally, the induction of RTP4 gene expression. Based on these results, we speculate that RTP4 functions as an inflammation-responsive molecule in the brain. However, further research is needed to fully understand its role. Full article

Background: Rheumatoid arthritis (RA) is a common systemic autoimmune inflammatory disease that can cause joint damage. We have recently reported that oral magnesium supplementation significantly reduces disease severity and joint damage in models of RA. Methods: In the present study, we analyzed the transcriptome of spleens and synovial tissues obtained from mice with KRN serum-induced arthritis (KSIA) consuming either a high Mg supplemented diet (Mg2800; n = 7) or a normal diet (Mg500; n = 7). Tissues were collected at the end of a 15-day KSIA experiment. RNA was extracted and used for sequencing and analyses. Results: There was an enrichment of differentially expressed genes (DEGs) belonging to Reactome and Gene Ontology (GO) pathways implicated in RA pathogenesis such as RHO GTPases, the RUNX1 pathway, oxidative stress-induced senescence, and the senescence-associated secretory phenotype. Actc1 and Nr4a3 were among the genes with the highest expression, while Krt79 and Ffar2 were among the genes with the lowest expression in synovial tissues of the Mg2800 group compared with the Mg500 group. Spleens had an enrichment for the metabolism of folate and pterines and the HSP90 chaperone cycle for the steroid hormone receptor. Conclusions: We describe the tissue transcriptomic consequences of arthritis-protecting Mg supplementation in KSIA mice. These results show that oral Mg supplementation may interfere with the response to oxidative stress and senescence and other processes known to participate in RA pathogenesis. We provide new evidence supporting the disease-suppressing effect of increased Mg intake in arthritis and its potential to become a new addition to the therapeutic options for RA and other autoimmune and inflammatory diseases. Full article

Background/Objectives: There is increasing evidence linking circulating neurotoxic lipids to the progression of chronic neuroinflammatory diseases in the peripheral and central nervous systems. Strategies to modify lipid profiles, such as docosahexaenoic acid (DHA)-rich supplementation, may aid in managing conditions like painful diabetic neuropathy (pDN). In a previous study, we demonstrated that three months of DHA supplementation significantly altered the metabolomic profile of patients with painful diabetic neuropathy (pDN), resulting in symptom improvement. This study investigates whether DHA-rich supplementation reduces neurotoxic lipid mediators associated with pDN in individuals with type 2 diabetes mellitus (T2DM). Methods: Forty individuals with type 2 diabetes participated in the “En Balance-PLUS” study, attending weekly lifestyle and nutrition education sessions while receiving daily supplementation of 1000 mg DHA and 200 mg EPA. Pain levels were assessed using the Short-Form McGill Pain Questionnaire (SF-MPQ) at baseline and after three months. Blood serum samples collected at these time points underwent untargeted lipidomic analyses, with ELISA used to evaluate biomarkers of necrosis (MLKL), autophagy (ATG5), and lipid chaperone protein (FABP5). Results: Untargeted lipidomic analysis revealed that several neurotoxic-associated lipids significantly decreased after DHA-rich supplementation. Also, circulating levels of MLKL were reduced, while protein levels of ATG5 and FABP5 significantly increased. Conclusions: The reduction of circulating neurotoxic lipids and increase in neuroprotective lipids following DHA-rich supplementation are consistent with the reported roles of omega-3 polyunsaturated fatty acids (PUFAs) in reducing adverse symptoms associated with neuroinflammatory diseases and painful neuropathy. Full article

In Alzheimer’s disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S proteasome, macroautophagy, and aggrephagy. Neurofibrillary tangles (NFTs) form upon the impairment of aggrephagy, and eventually, the ubiquitin chaperone valosin-containing protein (VCP) and heat shock 70 kDa protein (HSP70) are recruited to the sites of NFTs for the extraction of tau for the ubiquitin–proteasome system (UPS)-mediated degradation. However, the impairment of tau degradation in neurons allows tau to be secreted into the extracellular space. Secreted tau can be monomers, oligomers, and paired helical filaments (PHFs), which are seeding competent pathological tau that can be endocytosed/phagocytosed by healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), and oligodendrocytes, often causing proteotoxic stress and eventually triggers senescence. Senescent cells secrete various senescence-associated secretory phenotype (SASP) factors, which trigger cellular atrophy, causing decreased brain volume in human AD. However, the molecular mechanisms of proteotoxic stress and cellular senescence are not entirely understood and are an emerging area of research. Therefore, this comprehensive review summarizes pertinent studies that provided evidence for the sequential tau degradation, failure, and the mechanistic link between tau-driven proteotoxic stress and cellular senescence in AD. Full article

Fatty acid binding protein 7 (FABP7) is a multifunctional chaperone involved in lipid metabolism and signaling. It is primarily expressed in astrocytes and neural stem cells (NSCs), as well as their derived malignant glioma cells within the central nervous system. Despite growing evidence for FABP7’s tumor-intrinsic onco-metabolic functions, its mechanistic role in regulating the brain tumor immune microenvironment (TIME) and its impact on prognosis at the molecular level remain incompletely understood. Utilizing combined transcriptome profiling and pan-cancer analysis approaches, we report that FABP7 mediates the expression of multiple onco-immune drivers, collectively impacting tumor immunity and clinical outcomes across brain cancer subtypes. An analysis of a single-cell expression atlas revealed that FABP7 is predominantly expressed in the glial lineage and malignant cell populations in gliomas, with nuclear localization in their parental NSCs. Pathway and gene enrichment analysis of RNA sequencing data from wild-type (WT) and Fabp7-knockout (KO) mouse brains, alongside control (CTL) and FABP7-overexpressing (FABP7 OV) human astrocytes, revealed a more pronounced effect of FABP7 levels on multiple cancer-associated pathways. Notably, genes linked to brain cancer progression and tumor immunity (ENO1, MUC1, COL5A1, and IL11) were significantly downregulated (>2-fold) in KO brain tissue but were upregulated in FABP7 OV astrocytes. Furthermore, an analysis of data from The Cancer Genome Atlas (TCGA) showed robust correlations between the expression of these factors, as well as FABP7, and established glioma oncogenes (EGFR, BRAF, NF1, PDGFRA, IDH1), with stronger associations seen in low-grade glioma (LGG) than in glioblastoma (GBM). TIME profiling also revealed that the expression of FABP7 and the genes that it modulates was significantly associated with prognosis and survival, particularly in LGG patients, by influencing the infiltration of immunosuppressive cell populations within tumors. Overall, our findings suggest that FABP7 acts as an intracellular regulator of pro-tumor immunomodulatory genes, exerting a synergistic effect on the TIME and clinical outcomes in brain cancer subtypes. Full article

Background: Recently identified Hero proteins, which possess chaperone-like functions, are promising candidates for research into atherosclerosis-related diseases, including ischemic stroke (IS). Methods: 2204 Russian subjects (917 IS patients and 1287 controls) were genotyped for fifteen common SNPs in Hero20 gene C11orf58 using probe-based PCR and the MassArray-4 system. Results: Six C11orf58 SNPs were significantly associated with an increased risk of IS in the overall group (OG) and significantly modified by smoking (SMK) and low fruit/vegetable intake (LFVI): rs10766342 (effect allele (EA) A; P(_OG = 0.02; _SMK = 0.009; _LFVI = 0.04)), rs11024032 (EA T; P(_OG = 0.01; _SMK = 0.01; _LFVI = 0.036)), rs11826990 (EA G; P(_OG = 0.007; _SMK = 0.004; _LFVI = 0.03)), rs3203295 (EA C; P(_OG = 0.016; _SMK = 0.01; _LFVI = 0.04)), rs10832676 (EA G; P(_OG = 0.006; _SMK = 0.002; _LFVI = 0.01)), rs4757429 (EA T; P(_OG = 0.02; _SMK = 0.04; _LFVI = 0.04)). The top ten intergenic interactions of Hero genes (two-, three-, and four-locus models) involved exclusively polymorphic loci of C11orf58 and C19orf53 and were characterized by synergic and additive (independent) effects between SNPs. Conclusions: Thus, C11orf58 gene polymorphism represents a major risk factor for IS. Bioinformatic analysis showed the involvement of C11orf58 SNPs in molecular mechanisms of IS mediated by their role in the regulation of redox homeostasis, inflammation, vascular remodeling, apoptosis, vasculogenesis, neurogenesis, lipid metabolism, proteostasis, hypoxia, cell signaling, and stress response. In terms of intergenic interactions, C11orf58 interacts most closely with C19orf53. Full article

As areas of application of terahertz (THz) radiation expand in science and practice, evidence is accumulating that this type of radiation can affect not only biological molecules directly, but also cellular processes as a whole. In this study, the transcriptome in cells of the thermophilic bacterium Geobacillus icigianus was analyzed immediately after THz irradiation (0.23 W/cm², 130 μm, 15 min) and at 10 min after its completion. THz irradiation does not affect the activity of heat shock protein genes and diminishes the activity of genes whose products are involved in peptidoglycan recycling, participate in redox reactions, and protect DNA and proteins from damage, including genes of chaperone protein ClpB and of DNA repair protein RadA, as well as genes of catalase and kinase McsB. Gene systems responsible for the homeostasis of transition metals (copper, iron, and zinc) proved to be the most sensitive to THz irradiation; downregulation of these systems increased significantly 10 min after the end of the irradiation. It was also hypothesized that some negative effects of THz radiation on metabolism in G. icigianus cells are related to disturbances in activities of gene systems controlled by metal-sensitive transcription factors. Full article

Heat shock proteins (Hsps), acting as molecular chaperones, play a pivotal role in plant responses to environmental stress. In this study, we found a total of 192 genes encoding Hsps, which are distributed across all 12 chromosomes, with higher concentrations on chromosomes 1, 2, 3, and 5. These Hsps can be divided into six subfamilies (sHsp, Hsp40, Hsp60, Hsp70, Hsp90, and Hsp100) based on molecular weight and homology. Expression pattern data indicated that these Hsp genes can be categorized into three groups: generally high expression in almost all tissues, high tissue-specific expression, and low expression in all tissues. Further analysis of 15 representative genes found that the expression of 14 Hsp genes was upregulated by high temperatures. Subcellular localization analysis revealed seven proteins localized to the endoplasmic reticulum, while others localized to the mitochondria, chloroplasts, and nucleus. We successfully obtained the knockout mutants of above 15 Hsps by the CRISPR/Cas9 gene editing system. Under natural high-temperature conditions, the mutants of eight Hsps showed reduced yield mainly due to the seed setting rate or grain weight. Moreover, the rice quality of most of these mutants also changed, including increased grain chalkiness, decreased amylose content, and elevated total protein content, and the expressions of starch metabolism-related genes in the endosperm of these mutants were disturbed compared to the wild type under natural high-temperature conditions. In conclusion, our study provided new insights into the HSP gene family and found that it plays an important role in the formation of rice quality and yield. Full article

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining neural homeostasis but can also contribute to disease and injury when this state is disrupted or conversely play a pivotal role in neurorepair. One way that microglia exert their effects is through the secretion of small vesicles, microglia-derived exosomes (MGEVs). Exosomes facilitate intercellular communication through transported cargoes of proteins, lipids, RNA, and other bioactive molecules that can alter the behavior of the cells that internalize them. Under normal physiological conditions, MGEVs are essential to homeostasis, whereas the dysregulation of their production and/or alterations in their cargoes have been implicated in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), spinal cord injury (SCI), and traumatic brain injury (TBI). In contrast, MGEVs may also offer therapeutic potential by reversing inflammation or being amenable to engineering for the delivery of beneficial biologics or drugs. The effects of MGEVs are determined by the phenotypic state of the parent microglia. Exosomes from anti-inflammatory or pro-regenerative microglia support neurorepair and cell survival by delivering neurotrophic factors, anti-inflammatory mediators, and molecular chaperones. Further, MGEVs can also deliver components like mitochondrial DNA (mtDNA) and proteins to damaged neurons to enhance cellular metabolism and resilience. MGEVs derived from pro-inflammatory microglia can have detrimental effects on neural health. Their cargo often contains pro-inflammatory cytokines, molecules involved in oxidative stress, and neurotoxic proteins, which can exacerbate neuroinflammation, contribute to neuronal damage, and impair synaptic function, hindering neurorepair processes. The role of MGEVs in neurodegeneration and injury—whether beneficial or harmful—largely depends on how they modulate inflammation through the pro- and anti-inflammatory factors in their cargo, including cytokines and microRNAs. In addition, through the propagation of pathological proteins, such as amyloid-beta and alpha-synuclein, MGEVs can also contribute to disease progression in disorders such as AD and PD, or by the transfer of apoptotic or necrotic factors, they can induce neuron toxicity or trigger glial scarring during neurological injury. In this review, we have provided a comprehensive and up-to-date understanding of the molecular mechanisms underlying the multifaceted role of MGEVs in neurological injury and disease. In particular, the role that specific exosome cargoes play in various pathological conditions, either in disease progression or recovery, will be discussed. The therapeutic potential of MGEVs has been highlighted including potential engineering methodologies that have been employed to alter their cargoes or cell-selective targeting. Understanding the factors that influence the balance between beneficial and detrimental exosome signaling in the CNS is crucial for developing new therapeutic strategies for neurodegenerative diseases and neurotrauma. Full article

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays crucial roles in surfactant and protein synthesis, assisting mitochondrial function, and maintaining metabolic homeostasis. Under OS, disturbed metabolism and protein folding transform the ER structure to refold proteins and help degrade non-essential proteins to resume cell homeostasis. When OS becomes excessive, the endogenous chaperone will leave the three ER stress sensors to allow subsequent changes, including cell death and senescence, impairing the growth potential of organs. The contributing role of ER stress in BPD is confirmed by reproducing the BPD phenotype in rat pups by ER stress inducers. Although chemical chaperones attenuate BPD, ER stress is still associated with cellular senescence. N-acetyl-lysyltyrosylcysteine amide (KYC) is a myeloperoxidase inhibitor that attenuates ER stress and senescence as a systems pharmacology agent. In this review, we describe the role of ER stress in BPD and discuss the therapeutic potentials of chemical chaperones and KYC, highlighting their promising role in future therapeutic interventions. Full article