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International Journal of Molecular... Jun 2024Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the...
Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, . However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by and mutations, whereas -linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in - and -mutant fibroblasts than -mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than -mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare and biallelic pathogenic variants in comparison with the profile observed in -linked GCase deficiency.
Topics: Glucosylceramidase; Humans; Gaucher Disease; Saposins; Lysosomal Membrane Proteins; Receptors, Scavenger; Fibroblasts; Mutation; Lysosomes; Hexosaminidases; Male; Female
PubMed: 38928321
DOI: 10.3390/ijms25126615 -
International Journal of Molecular... Jun 2024Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and...
Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and induces reactive oxygen species (ROS), leading to cellular damage. This study explores the relationship between HBx-induced ROS, p53 activation, and HBV replication. Using HepG2 and Hep3B cell lines that express the HBV receptor NTCP, we compared ROS generation and HBV replication relative to p53 status. Results indicated that HBV infection significantly increased ROS levels in p53-positive HepG2-NTCP cells compared to p53-deficient Hep3B-NTCP cells. Knockdown of p53 reduced ROS levels and enhanced HBV replication in HepG2-NTCP cells, whereas p53 overexpression increased ROS and inhibited HBV replication in Hep3B-NTCP cells. The ROS scavenger N-acetyl-L-cysteine (NAC) reversed these effects. The study also found that ROS-induced degradation of the HBx is mediated by the E3 ligase Siah-1, which is activated by p53. Mutations in p53 or inhibition of its transcriptional activity prevented ROS-mediated HBx degradation and HBV inhibition. These findings reveal a p53-dependent negative feedback loop where HBx-induced ROS increases p53 levels, leading to Siah-1-mediated HBx degradation and HBV replication inhibition. This study offers insights into the molecular mechanisms of HBV replication and identifies potential therapeutic targets involving ROS and p53 pathways.
Topics: Humans; Tumor Suppressor Protein p53; Hepatitis B virus; Reactive Oxygen Species; Virus Replication; Trans-Activators; Viral Regulatory and Accessory Proteins; Hep G2 Cells; Liver Neoplasms; Carcinoma, Hepatocellular; Ubiquitin-Protein Ligases; Nuclear Proteins; Cell Line, Tumor
PubMed: 38928309
DOI: 10.3390/ijms25126606 -
International Journal of Molecular... Jun 2024Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized...
Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized endoplasmic reticulum (ER) in fibroblasts from COPD with different responses to chemical stressors compared to healthy subjects. Here, we aimed to investigate differences in stress-related gene expressions within lung cells from COPD and healthy subjects. Bronchoalveolar lavage (BAL) cells were collected from seven COPD and 35 healthy subjects. Lung fibroblasts were derived from 19 COPD and 24 healthy subjects and exposed to cigarette smoke extract (CSE). Gene and protein expression and cell proliferation were investigated. Compared to healthy subjects, we found lower gene expression of CHOP in lung fibroblasts from COPD subjects. Exposure to CSE caused inhibition of lung fibroblast proliferation in both groups, though the changes in ER stress-related gene expressions (ATF6, IRE1, PERK, ATF4, CHOP, BCL2L1) and genes relating to proteasomal subunits mostly occurred in healthy lung fibroblasts. No differences were found in BAL cells. In this study, we have found that lung fibroblasts from COPD subjects have an atypical ER stress gene response to CSE, particularly in genes related to apoptosis. This difference in response to CSE may be a contributing factor to COPD progression.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Fibroblasts; Endoplasmic Reticulum Stress; Male; Female; Middle Aged; Lung; Bronchoalveolar Lavage Fluid; Aged; Cell Proliferation; Gene Expression Regulation; Cells, Cultured; Apoptosis; Case-Control Studies
PubMed: 38928305
DOI: 10.3390/ijms25126600 -
International Journal of Molecular... Jun 2024The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids,... (Review)
Review
The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.
Topics: Humans; Antineoplastic Agents; Peripheral Nervous System Diseases; Ion Channels; Animals; Neurotoxicity Syndromes; Membrane Transport Proteins; Neoplasms
PubMed: 38928257
DOI: 10.3390/ijms25126552 -
International Journal of Molecular... Jun 2024Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this...
Proteasome 26S Subunit, Non-ATPase 9 () plays an important role in the balance of protamine and the stability of the nucleolar structure during spermatogenesis. In this study, we cloned the of and analyzed its expression pattern. was identified on the Z chromosome of , which is considered an interesting candidate gene for spermatogenesis. qRT-PCR and FISH experiments showed that the gene was significantly highly expressed in the testes. It is worth noting that the expression level of in male fish testes is significantly higher than that in pseudomales. In order to further explore the role of in spermatogenesis, a male testicular cell line was used as the experimental material. The results of the -RNAi and overexpression experiments showed that had a synergistic effect with spermatogenesis-related genes , , and , but had an antagonistic effect with . Our findings offer a scientific foundation for comprehending the role of in the spermatogenesis regulatory network of .
Topics: Animals; Spermatogenesis; Male; Testis; Sex Chromosomes; Fish Proteins; Proteasome Endopeptidase Complex; Cloning, Molecular
PubMed: 38928079
DOI: 10.3390/ijms25126372 -
Genes Jun 2024We conducted transcriptome sequencing on salt-tolerant mutants X5 and X3, and a control (Ctr) strain of after treatment with artificial seawater at varying salinities...
We conducted transcriptome sequencing on salt-tolerant mutants X5 and X3, and a control (Ctr) strain of after treatment with artificial seawater at varying salinities (30‱, 45‱, and 60‱) for 3 weeks. Differentially expressed genes were identified and a weighted co-expression network analysis was conducted. The blue, red, and tan modules were most closely associated with salinity, while the black, cyan, light cyan, and yellow modules showed a close correlation with strain attributes. KEGG enrichment of genes from the aforementioned modules revealed that the key enrichment pathways for salinity attributes included the proteasome and carbon fixation in photosynthesis, whereas the key pathways for strain attributes consisted of lipid metabolism, oxidative phosphorylation, soluble N-ethylmaleimide-sensitive factor-activating protein receptor (SNARE) interactions in vesicular transport, and porphyrin and chlorophyll metabolism. Gene expression for the proteasome and carbon fixation in photosynthesis was higher in all strains at 60‱. In addition, gene expression in the proteasome pathway was higher in the X5-60 than Ctr-60 and X3-60. Based on the above data and relevant literature, we speculated that mutant X5 likely copes with high salt stress by upregulating genes related to lysosome and carbon fixation in photosynthesis. The proteasome may be reset to adjust the organism's proteome composition to adapt to high-salt environments, while carbon fixation may aid in maintaining material and energy metabolism for normal life activities by enhancing carbon dioxide uptake via photosynthesis. The differences between the X5-30 and Ctr-30 expression of genes involved in the synthesis of secondary metabolites, oxidative phosphorylation, and SNARE interactions in vesicular transport suggested that the X5-30 may differ from Ctr-30 in lipid metabolism, energy metabolism, and vesicular transport. Finally, among the key pathways with good correlation with salinity and strain traits, the key genes with significant correlation with salinity and strain traits were identified by correlation analysis.
Topics: Salt Tolerance; Transcriptome; Gene Regulatory Networks; Salinity; Photosynthesis; Osmotic Pressure; Proteasome Endopeptidase Complex; Gene Expression Profiling; Lipid Metabolism
PubMed: 38927717
DOI: 10.3390/genes15060781 -
Biomedicines Jun 2024We explored differences in the DNA methylation statuses of , , , and gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR)...
We explored differences in the DNA methylation statuses of , , , and gene promoter regions in patients with type 1 diabetes and different diabetic retinopathy (DR) stages. Study subjects included individuals with no DR (NDR, = 41), those with non-proliferative DR (NPDR, = 27), and individuals with proliferative DR or those who underwent laser photocoagulation (PDR/LPC, = 46). DNA methylation was determined by Zymo OneStep qMethyl technique. The methylation of (NDR 5.9 (3.9-8.7) %, NPDR 4.5 (3.8-5.7) %, PDR/LPC 6.6 (4.7-10.7) %, = 0.003) and (NDR 2.2 (1.9-3.7) %, NPDR 2.2 (1.9-3.0) %, PDR/LPC 3.2 (2.5-7.1) %, < 0.01) differed across the groups. Consistent correlations were observed between the methylation levels of and in all study groups. DNA methylation levels of , , and genes were positively correlated with the duration of diabetes, HbA1c, and albuminuria in certain study groups. Univariate regression models revealed a significant association between the methylation level z-scores of , , and and severe DR (: OR = 1.96 (1.15; 3.33), = 0.013; : OR = 1.90 (1.14; 3.16), = 0.013; : OR = 3.19 (1.26; 8.06), = 0.014). remained significantly associated with DR in multivariate analysis. Our findings suggest significant associations between the severity of DR and the DNA methylation levels of the genes , , and , but not gene.
PubMed: 38927561
DOI: 10.3390/biomedicines12061354 -
Biomolecules May 2024The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations... (Review)
Review
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
Topics: Humans; Tumor Suppressor Protein p53; Neoplasms; Tumor Microenvironment; Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Animals; Mutation; Lysosomes; Carcinogenesis
PubMed: 38927053
DOI: 10.3390/biom14060649 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs,... (Review)
Review
Multiple myeloma (MM) is an incurable malignant plasma cell diseases, the incidence of which is increasing year by year. The application of immunomodulators drugs, proteasome inhibitors, anti-CD38 antibodies, CAR-T, and HSCT have significantly improved the prognosis of patients with MM, however new therapeutic tools need to be developed to improve the prognosis of patients with relapsed/refractory after conventional regimens treatment. Bispecific antibodies are a novel immunotherapeutic approach that generates immune synapses by binding to targets on malignant plasma cells and cytotoxic immune effector cells (T cells/natural killer cells), leading to T/NK cells activation and malignant plasma cell lysis. Several preclinical and phase I clinical studies have shown good efficacy, bringing new possibilities for patients with relapsed/refractory MM to improve their prognosis in the future in combination with the rest of the treatment options. This article summarizes the classification of bispecific antibodies developed in recent years, and the results of preclinical and clinical trials, which will provide some reference for treating MM.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Immunotherapy; Killer Cells, Natural; Prognosis; T-Lymphocytes
PubMed: 38926994
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.046 -
Scientific Reports Jun 2024Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones...
Excess amounts of histones in the cell induce mitotic chromosome loss and genomic instability, and are therefore detrimental to cell survival. In yeast, excess histones are degraded by the proteasome mediated via the DNA damage response factor Rad53. Histone expression, therefore, is tightly regulated at the protein level. Our understanding of the transcriptional regulation of histone genes is far from complete. In this study, we found that calcineurin inhibitor treatment increased histone protein levels, and that the transcription factor NFATc1 (nuclear factor of activated T cells 1) repressed histone transcription and acts downstream of the calcineurin. We further revealed that NFATc1 binds to the promoter regions of many histone genes and that histone transcription is downregulated in a manner dependent on intracellular calcium levels. Indeed, overexpression of histone H3 markedly inhibited cell proliferation. Taken together, these findings suggest that NFATc1 prevents the detrimental effects of histone H3 accumulation by inhibiting expression of histone at the transcriptional level.
Topics: NFATC Transcription Factors; Histones; Calcineurin; Humans; Cell Proliferation; Gene Expression Regulation; Promoter Regions, Genetic; Signal Transduction; Transcription, Genetic; Calcium
PubMed: 38926604
DOI: 10.1038/s41598-024-65769-9