-
Frontiers in Cardiovascular Medicine 2024Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to the accumulation of globotriaosylceramide (Gb3) and... (Review)
Review
Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), culminating in various clinical signs and symptoms that significantly impact quality of life. Although treatments such as enzyme replacement, oral chaperone, and emerging therapies like gene therapy exist; delayed diagnosis often curtails their effectiveness. Our review highlights the importance of delineating the stages of inflammation in Fabry disease to enhance the timing and efficacy of diagnosis and interventions, particularly before the progression to fibrosis, where treatment options are less effective. Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms that remain poorly understood. Highlighted by the fact that Fabry disease shares immune profiles with systemic autoinflammatory diseases, blurring the distinctions between these disorders and highlighting the need for a nuanced understanding of immune dynamics. This insight is crucial for developing targeted therapies and improving the administration of current treatments like enzyme replacement. Moreover, our review discusses the complex interplay between these inflammatory processes and current treatments, such as the challenges posed by anti-drug antibodies. These antibodies can attenuate the effectiveness of therapies, necessitating more refined approaches to mitigate their impact. By advancing our understanding of the molecular changes, inflammatory mediators and causative factors that drive inflammation in Fabry disease, we aim to clarify their role in the disease's progression. This improved understanding will help us see how these processes fit into the current landscape of Fabry disease. Additionally, it will guide the development of more effective diagnostic and therapeutic approaches, ultimately improving patient care.
PubMed: 38932991
DOI: 10.3389/fcvm.2024.1420067 -
Emerging Microbes & Infections Dec 2024A positive-sense (+) single-stranded RNA (ssRNA) virus (e.g. enterovirus A71, EV-A71) depends on viral polypeptide translation for initiation of virus replication after...
A positive-sense (+) single-stranded RNA (ssRNA) virus (e.g. enterovirus A71, EV-A71) depends on viral polypeptide translation for initiation of virus replication after entry. We reported that EV-A71 hijacks Hsp27 to induce hnRNP A1 cytosol redistribution to initiate viral protein translation, but the underlying mechanism is still elusive. Here, we show that phosphorylation-deficient Hsp27-3A (Hsp27) and Hsp27 fail to translocate into the nucleus and induce hnRNP A1 cytosol redistribution, while Hsp27 and Hsp27 display similar effects to the wild type Hsp27. Furthermore, we demonstrate that the viral 2A protease (2A) activity is a key factor in regulating Hsp27/hnRNP A1 relocalization. Hsp27 dramatically decreases the IRES activity and viral replication, which are partially reduced by Hsp27. However, Hsp27 displays the same activity as the wild-type Hsp27. Peptide S78 potently suppresses EV-A71 protein translation and reproduction through blockage of EV-A71-induced Hsp27 phosphorylation and Hsp27/hnRNP A1 relocalization. A point mutation (S78A) on S78 impairs its inhibitory functions on Hsp27/hnRNP A1 relocalization and viral replication. Taken together, we demonstrate the importance of Ser78 phosphorylation of Hsp27 regulated by virus infection in nuclear translocation, hnRNP A1 cytosol relocation, and viral replication, suggesting a new path (such as peptide S78) for target-based antiviral strategy.
Topics: Enterovirus A, Human; Phosphorylation; Humans; Virus Replication; Heterogeneous Nuclear Ribonucleoprotein A1; HSP27 Heat-Shock Proteins; Enterovirus Infections; Antiviral Agents; Viral Proteins; Serine; HeLa Cells; Protein Biosynthesis; Cysteine Endopeptidases; Molecular Chaperones; Heat-Shock Proteins
PubMed: 38932432
DOI: 10.1080/22221751.2024.2368221 -
Viruses Jun 2024The mode and outcome of fish-virus interactions are influenced by many abiotic factors, among which water temperature is especially important in poikilothermic fish....
The mode and outcome of fish-virus interactions are influenced by many abiotic factors, among which water temperature is especially important in poikilothermic fish. Rare minnow is a eurythermal small cyprinid fish that is sensitive to infection with genotype II grass carp reovirus (GCRV). HSP70, a conservative and key player in heat shock response, is previously identified as an induced pro-viral factor during GCRV infection in vitro. Here, rare minnow was subjected to heat shock treatment (HST), 1 h treatment at 32 °C followed by reverting to a normal temperature of 24 °C, and subsequently challenged with GCRV-II at a dosage of 1 × LD. The effect of HST on GCRV virulence in vivo was evaluated by calculating virus-associated mortality and viral load in both dead and survival fish. The results revealed that HST enhanced the mortality of rare minnow infected with GCRV; the fact that viral loads in the tissue samples of HST-treated fish were significantly higher than those in samples of the control group at 6, 8 d p.i. reflected a faster infection process due to HST. Quantitative gene expression analysis was further employed to show that the expression levels of in intestine and liver tissues from the HST group declined faster than muscle tissue after HST. HST W/O GCRV challenge upregulated proinflammatory cytokines such as and , which was in consistence with the inflammation observed in histopathological analysis. This study shed light on the complexity of the interaction between fish abiotic and biotic stress response, which suggested that HST, an abiotic stress, could enhance the virulence of GCRV in that involved modulating the gene expression of host heat shock, as well as a pro-inflammatory response.
Topics: Animals; Fish Diseases; Reoviridae; Virulence; Reoviridae Infections; Cyprinidae; Viral Load; Carps; Heat-Shock Response; HSP70 Heat-Shock Proteins; Hot Temperature
PubMed: 38932213
DOI: 10.3390/v16060921 -
International Journal of Molecular... Jun 2024The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter... (Review)
Review
The incorporation of histone variants has structural ramifications on nucleosome dynamics and stability. Due to their unique sequences, histone variants can alter histone-histone or histone-DNA interactions, impacting the folding of DNA around the histone octamer and the overall higher-order structure of chromatin fibers. These structural modifications alter chromatin compaction and accessibility of DNA by transcription factors and other regulatory proteins to influence gene regulatory processes such as DNA damage and repair, as well as transcriptional activation or repression. Histone variants can also generate a unique interactome composed of histone chaperones and chromatin remodeling complexes. Any of these perturbations can contribute to cellular plasticity and the progression of human diseases. Here, we focus on a frequently overlooked group of histone variants lying within the four human histone gene clusters and their contribution to breast cancer.
Topics: Humans; Breast Neoplasms; Histones; Female; Chromatin Assembly and Disassembly; Chromatin; Nucleosomes; Multigene Family
PubMed: 38928493
DOI: 10.3390/ijms25126788 -
International Journal of Molecular... Jun 2024Although the moderate thermal stimulation of articular cartilage exerts chondroprotective effects, it is difficult to effectively heat deep articular cartilage with...
Although the moderate thermal stimulation of articular cartilage exerts chondroprotective effects, it is difficult to effectively heat deep articular cartilage with conventional methods. Photosensitizers increase the ambient temperature using near-infrared (NIR) radiation, which has high tissue permeability. We hypothesized that the intra-articular administration of photosensitizers and NIR irradiation would exert a greater heating effect on articular cartilage. We aimed to evaluate the heating effect of this method on cultured chondrocytes and rat knee cartilage. In vitro, we irradiated a photosensitizer-containing medium with NIR and measured changes in the medium temperature, cytotoxicity, and gene expression of heat shock protein () and aggrecan (). In vivo, the knee joints of rats treated with photosensitizers were irradiated with NIR, and changes in intra-articular temperature and gene expression were measured, alongside histological analysis. The results showed that the medium and intra-articular temperature were raised to approximately 40 °C with no apparent disruption to articular cartilage or the immunohistochemically enhanced staining of HSP70 in chondrocytes. The gene expression of and was increased in both cultured and articular cartilage. In summary, this method can safely heat joints and enhance cartilage metabolism by inducing HSP70 expression in articular cartilage. It presents a new hyperthermia therapy with effective cartilage protection.
Topics: Animals; Rats; Cartilage, Articular; Chondrocytes; Photosensitizing Agents; HSP70 Heat-Shock Proteins; Aggrecans; Male; Cells, Cultured; Rats, Sprague-Dawley; Infrared Rays; Hyperthermia, Induced
PubMed: 38928434
DOI: 10.3390/ijms25126728 -
International Journal of Molecular... Jun 2024A homozygous mutation of the gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations...
A homozygous mutation of the gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations induce the neurodegeneration of dopaminergic cells by reducing the protein expression of functional DNAJC6 and causing DNAJC6 paucity, an in vitro PARK19 model was constructed by using shRNA-mediated gene silencing of endogenous DANJC6 in differentiated human SH-SY5Y dopaminergic neurons. shRNA targeting DNAJC6 induced the neurodegeneration of dopaminergic cells. DNAJC6 paucity reduced the level of cytosolic clathrin heavy chain and the number of lysosomes in dopaminergic neurons. A DNAJC6 paucity-induced reduction in the lysosomal number downregulated the protein level of lysosomal protease cathepsin D and impaired macroautophagy, resulting in the upregulation of pathologic α-synuclein or phospho-α-synuclein in the endoplasmic reticulum (ER) and mitochondria. The expression of α-synuclein shRNA or cathepsin D blocked the DNAJC6 deficiency-evoked degeneration of dopaminergic cells. An increase in ER α-synuclein or phospho-α-synuclein caused by DNAJC6 paucity activated ER stress, the unfolded protein response and ER stress-triggered apoptotic signaling. The lack of DNAJC6-induced upregulation of mitochondrial α-synuclein depolarized the mitochondrial membrane potential and elevated the mitochondrial level of superoxide. The DNAJC6 paucity-evoked ER stress-related apoptotic cascade, mitochondrial malfunction and oxidative stress induced the degeneration of dopaminergic neurons via activating mitochondrial pro-apoptotic signaling. In contrast with the neuroprotective function of WT DNAJC6, the PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate the tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and stimulation of apoptotic signaling. Our data suggest that PARK19 mutation-induced DNAJC6 paucity causes the degeneration of dopaminergic neurons via downregulating protease cathepsin D and upregulating neurotoxic α-synuclein. Our results also indicate that PARK19 mutation (Q789X or R927G) impairs the DNAJC6-mediated neuroprotective function.
Topics: Cathepsin D; Dopaminergic Neurons; Humans; alpha-Synuclein; HSP40 Heat-Shock Proteins; Endoplasmic Reticulum Stress; Up-Regulation; Parkinson Disease; Mitochondria; Lysosomes; Down-Regulation; Apoptosis; Cell Line, Tumor
PubMed: 38928416
DOI: 10.3390/ijms25126711 -
International Journal of Molecular... Jun 2024It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid...
It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis. The molecular chaperone HSP60 alone induces inflammatory cytokine IL-6 and the co-chaperone HSP10 alone inhibits IL-6 induction. HSP60 and HSP10 form a complex in the presence of ATP. We analyzed the effects of Mizoribine, which is structurally similar to ATP, on the structure and physiological functions of HSP60-HSP10 using Native/PAGE and transmission electron microscopy. At low concentrations of Mizoribine, no complex formation of HSP60-HSP10 was observed, nor was the expression of IL-6 affected. On the other hand, high concentrations of Mizoribine promoted HSP60-HSP10 complex formation and consequently suppressed IL-6 expression. Here, we propose a novel mechanism of immunosuppressive action of Mizoribine.
Topics: Ribonucleosides; Interleukin-6; Chaperonin 60; Humans; Immunosuppressive Agents; Animals; Mice
PubMed: 38928158
DOI: 10.3390/ijms25126452 -
International Journal of Molecular... Jun 2024Histone chaperones are integral to chromatin dynamics, facilitating the assembly and disassembly of nucleosomes, thereby playing a crucial role in regulating gene... (Review)
Review
Histone chaperones are integral to chromatin dynamics, facilitating the assembly and disassembly of nucleosomes, thereby playing a crucial role in regulating gene expression and maintaining genomic stability. Moreover, they prevent aberrant histone interactions prior to chromatin assembly. Disruption in histone chaperone function may result in genomic instability, which is implicated in pathogenesis. This review aims to elucidate the role of histone chaperones in cancer pathologies and explore their potential as therapeutic targets. Histone chaperones have been found to be dysregulated in various cancers, with alterations in expression levels, mutations, or aberrant interactions leading to tumorigenesis and cancer progression. In addition, this review intends to highlight the molecular mechanisms of interactions between histone chaperones and oncogenic factors, underscoring their roles in cancer cell survival and proliferation. The dysregulation of histone chaperones is significantly correlated with cancer development, establishing them as active contributors to cancer pathology and viable targets for therapeutic intervention. This review advocates for continued research into histone chaperone-targeted therapies, which hold potential for precision medicine in oncology. Future advancements in understanding chaperone functions and interactions are anticipated to lead to novel cancer treatments, enhancing patient care and outcomes.
Topics: Humans; Neoplasms; Histone Chaperones; Histones; Animals; Gene Expression Regulation, Neoplastic
PubMed: 38928110
DOI: 10.3390/ijms25126403 -
International Journal of Molecular... Jun 2024Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of...
Mutations in the gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with mutations and broaden the clinical spectrum. We suggest screening for in recessive CMT patients with complex phenotypes of ataxia and spasticity.
Topics: Humans; Male; Charcot-Marie-Tooth Disease; Female; Mutation; Adult; Republic of Korea; Muscle Spasticity; Heterozygote; Cohort Studies; Middle Aged; Magnetic Resonance Imaging; Heat-Shock Proteins; Pedigree; Exome Sequencing; Cerebellar Ataxia; Phenotype; Adolescent; Young Adult
PubMed: 38928084
DOI: 10.3390/ijms25126378 -
Biomedicines Jun 2024Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood...
Neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent debilitating conditions with complex, poorly understood pathologies. Epichaperomes, pathologic protein assemblies nucleated on key chaperones, have emerged as critical players in the molecular dysfunction underlying these disorders. In this study, we introduce the synthesis and characterization of clickable epichaperome probes, PU-TCO, positive control, and PU-NTCO, negative control. Through comprehensive in vitro assays and cell-based investigations, we establish the specificity of the PU-TCO probe for epichaperomes. Furthermore, we demonstrate the efficacy of PU-TCO in detecting epichaperomes in brain tissue with a cellular resolution, underscoring its potential as a valuable tool for dissecting single-cell responses in neurodegenerative diseases. This clickable probe is therefore poised to address a critical need in the field, offering unprecedented precision and versatility in studying epichaperomes and opening avenues for novel insights into their role in disease pathology.
PubMed: 38927459
DOI: 10.3390/biomedicines12061252