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Clinical and Translational Medicine Oct 2023To reveal whether gut microbiota and their metabolites are correlated with oocyte quality decline caused by circadian rhythm disruption, and to search possible...
OBJECTIVE
To reveal whether gut microbiota and their metabolites are correlated with oocyte quality decline caused by circadian rhythm disruption, and to search possible approaches for improving oocyte quality.
DESIGN
A mouse model exposed to continuous light was established. The oocyte quality, embryonic development, microbial metabolites and gut microbiota were analyzed. Intragastric administration of microbial metabolites was conducted to confirm the relationship between gut microbiota and oocyte quality and embryonic development.
RESULTS
Firstly, we found that oocyte quality and embryonic development decreased in mice exposed to continuous light. Through metabolomics profiling and 16S rDNA-seq, we found that the intestinal absorption capacity of vitamin D was decreased due to significant decrease of bile acids such as lithocholic acid (LCA), which was significantly associated with increased abundance of Turicibacter. Subsequently, the concentrations of anti-Mullerian hormone (AMH) hormone in blood and melatonin in follicular fluid were reduced, which is the main reason for the decline of oocyte quality and early embryonic development, and this was rescued by injection of vitamin D3 (VD3). Secondly, melatonin rescued oocyte quality and embryonic development by increasing the concentration of lithocholic acid and reducing the concentration of oxidative stress metabolites in the intestine. Thirdly, we found six metabolites that could rescue oocyte quality and early embryonic development, among which LCA of 30 mg/kg and NorDCA of 15 mg/kg had the best rescue effect.
CONCLUSION
These findings confirm the link between ovarian function and gut microbiota regulation by microbial metabolites and have potential value for improving ovary function.
Topics: Pregnancy; Female; Mice; Animals; Gastrointestinal Microbiome; Vitamin D; Bile Acids and Salts; Melatonin; Oocytes; Embryonic Development; Lithocholic Acid
PubMed: 37846137
DOI: 10.1002/ctm2.1236 -
Molecular & Cellular Proteomics : MCP Aug 2023Protein aggregation of amyloid-β peptides and tau are pathological hallmarks of Alzheimer's disease (AD), which are often resistant to detergent extraction and thus... (Meta-Analysis)
Meta-Analysis
Protein aggregation of amyloid-β peptides and tau are pathological hallmarks of Alzheimer's disease (AD), which are often resistant to detergent extraction and thus enriched in the insoluble proteome. However, additional proteins that coaccumulate in the detergent-insoluble AD brain proteome remain understudied. Here, we comprehensively characterized key proteins and pathways in the detergent-insoluble proteome from human AD brain samples using differential extraction, tandem mass tag (TMT) labeling, and two-dimensional LC-tandem mass spectrometry. To improve quantification accuracy of the TMT method, we developed a complement TMT-based strategy to correct for ratio compression. Through the meta-analysis of two independent detergent-insoluble AD proteome datasets (8914 and 8917 proteins), we identified 190 differentially expressed proteins in AD compared with control brains, highlighting the pathways of amyloid cascade, RNA splicing, endocytosis/exocytosis, protein degradation, and synaptic activity. To differentiate the truly detergent-insoluble proteins from copurified background during protein extraction, we analyzed the fold of enrichment for each protein by comparing the detergent-insoluble proteome with the whole proteome from the same AD samples. Among the 190 differentially expressed proteins, 84 (51%) proteins of the upregulated proteins (n = 165) were enriched in the insoluble proteome, whereas all downregulated proteins (n = 25) were not enriched, indicating that they were copurified components. The vast majority of these enriched 84 proteins harbor low-complexity regions in their sequences, including amyloid-β, Tau, TARDBP/TAR DNA-binding protein 43, SNRNP70/U1-70K, MDK, PTN, NTN1, NTN3, and SMOC1. Moreover, many of the enriched proteins in AD were validated in the detergent-insoluble proteome by five steps of differential extraction, proteomic analysis, or immunoblotting. Our study reveals a resource list of proteins and pathways that are exclusively present in the detergent-insoluble proteome, providing novel molecular insights to the formation of protein pathology in AD.
Topics: Humans; Alzheimer Disease; Proteome; Detergents; Proteomics; Tandem Mass Spectrometry; Brain; Ribonucleoprotein, U1 Small Nuclear
PubMed: 37356496
DOI: 10.1016/j.mcpro.2023.100608 -
International Immunology Apr 2024The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting... (Review)
Review
The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.
Topics: Humans; Particulate Matter; Vehicle Emissions; Tight Junctions; Allergens; Oxidative Stress; Epithelial Cells
PubMed: 38227765
DOI: 10.1093/intimm/dxae002 -
Analytical and Bioanalytical Chemistry Jul 2023Detergents enable the investigation of membrane proteins by mass spectrometry. Detergent designers aim to improve underlying methodologies and are confronted with the... (Review)
Review
Detergents enable the investigation of membrane proteins by mass spectrometry. Detergent designers aim to improve underlying methodologies and are confronted with the challenge to design detergents with optimal solution and gas-phase properties. Herein, we review literature related to the optimization of detergent chemistry and handling and identify an emerging research direction: the optimization of mass spectrometry detergents for individual applications in mass spectrometry-based membrane proteomics. We provide an overview about qualitative design aspects including their relevance for the optimization of detergents in bottom-up proteomics, top-down proteomics, native mass spectrometry, and Nativeomics. In addition to established design aspects, such as charge, concentration, degradability, detergent removal, and detergent exchange, it becomes apparent that detergent heterogeneity is a promising key driver for innovation. We anticipate that rationalizing the role of detergent structures in membrane proteomics will serve as an enabling step for the analysis of challenging biological systems.
Topics: Detergents; Proteomics; Mass Spectrometry; Membrane Proteins
PubMed: 36808272
DOI: 10.1007/s00216-023-04584-z -
Frontiers in Microbiology 2023Proteases (proteinases or peptidases) are a class of hydrolases that cleave peptide chains in proteins. Endopeptidases are a type of protease that hydrolyze the internal... (Review)
Review
Proteases (proteinases or peptidases) are a class of hydrolases that cleave peptide chains in proteins. Endopeptidases are a type of protease that hydrolyze the internal peptide bonds of proteins, forming shorter peptides; exopeptidases hydrolyze the terminal peptide bonds from the C-terminal or N-terminal, forming free amino acids. Microbial proteases are a popular instrument in many industrial applications. In this review, the classification, detection, identification, and sources of microbial proteases are systematically introduced, as well as their applications in food, detergents, waste treatment, and biotechnology processes in the industry fields. In addition, recent studies on techniques used to express heterologous microbial proteases are summarized to describe the process of studying proteases. Finally, future developmental trends for microbial proteases are discussed.
PubMed: 37779686
DOI: 10.3389/fmicb.2023.1236368 -
BioDrugs : Clinical Immunotherapeutics,... Jan 2024Outer membrane vesicles (OMVs) are spontaneously released by many gram-negative bacteria during their growth and constitute an important virulence factor for bacteria,... (Review)
Review
Outer membrane vesicles (OMVs) are spontaneously released by many gram-negative bacteria during their growth and constitute an important virulence factor for bacteria, helping them to survive through harsh environmental conditions. Native OMVs, naturally-released from bacteria, are produced at a level too low for vaccine manufacturing, requiring chemical treatment (detergent-extracted) or genetic manipulation, resulting in generalized modules for membrane antigens (GMMAs). Over the years, the nature and properties of OMVs have made them a viable platform for vaccine development. There are a few licensed OMV vaccines mainly for the prevention of meningitis caused by Neisseria meningitidis serogroup B (MenB) and Haemophilus influenzae type b (Hib). There are several candidates in clinical development against other gram-negative organisms from which the OMVs are derived, but also against heterologous targets in which the OMVs are used as carriers (e.g. coronavirus disease 2019 [COVID-19]). The use of OMVs for targets other than those from which they are derived is a major advancement in OMV technology, improving its versatility by being able to deliver protein or polysaccharide antigens. Other advances include the range of genetic modifications that can be made to improve their safety, reduce reactogenicity, and increase immunogenicity and protective efficacy. However, significant challenges remain, such as identification of general tools for high-content surface expression of heterologous proteins on the OMV surface. Here, we outline the progress of OMV vaccines to date, particularly discussing licensed OMV-based vaccines and candidates in clinical development. Recent trends in preclinical research are described, mainly focused on genetic manipulation and chemical conjugation for the use of OMVs as carriers for heterologous protein and polysaccharide antigens. Remaining challenges with the use of OMVs and directions for future research are also discussed.
Topics: Humans; Bacterial Outer Membrane Proteins; Vaccines; Polysaccharides
PubMed: 37796436
DOI: 10.1007/s40259-023-00627-0 -
Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.Brain : a Journal of Neurology Aug 2023Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent...
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
Topics: Humans; Mice; Animals; tau Proteins; Alzheimer Disease; RNA; Neurodegenerative Diseases; Detergents; Polymerization; Tauopathies; Brain; RNA, Messenger; Caenorhabditis elegans; Microtubules; Poly(A)-Binding Protein I
PubMed: 36732296
DOI: 10.1093/brain/awad032 -
Indian Journal of Ophthalmology Dec 2023Nowadays, people give more importance and pay closer attention to the condition of their eyelids and lid margins. This increased recognition of eyelid hygiene is due to... (Review)
Review
Nowadays, people give more importance and pay closer attention to the condition of their eyelids and lid margins. This increased recognition of eyelid hygiene is due to the growing awareness that improper eyelid cleaning might lead to various ocular surface diseases such as blepharitis and meibomian gland dysfunction. These ocular surface diseases can greatly affect people's quality of life. This article reviews the latest procedures for proper eyelid cleaning, including indications, methods, tools, detergents, and clinical applications, to maintain a healthy ocular surface and assist in the treatment of dry eye and blepharitis.
Topics: Humans; Quality of Life; Eyelids; Blepharitis; Meibomian Gland Dysfunction; Hygiene; Dry Eye Syndromes; Meibomian Glands; Eyelid Diseases; Tears
PubMed: 37991291
DOI: 10.4103/IJO.IJO_1457_23 -
BioRxiv : the Preprint Server For... Oct 2023Protein function strongly depends on temperature, which is related to temperature-dependent changes in the equilibria of protein conformational states. We leveraged...
Protein function strongly depends on temperature, which is related to temperature-dependent changes in the equilibria of protein conformational states. We leveraged variable-temperature F-NMR spectroscopy to interrogate the temperature dependence of the conformational landscape of the human A adenosine receptor (AAR), a class A GPCR. Temperature-induced changes in the conformational equilibria of AAR in lipid nanodiscs were markedly dependent on the efficacy of bound drugs. While antagonist complexes displayed only modest changes as the temperature rose, both full and partial agonist complexes exhibited substantial increases in the active state population. Importantly, the temperature-dependent response of complexes with both full and partial agonists exhibited a pronounced sensitivity to the specific membrane mimetic employed. In striking contrast to observations within lipid nanodiscs, in detergent micelles the active state population exhibited different behavior for AAR complexes with both full and partial agonists. This underscores the importance of the protein environment in understanding the thermodynamics of GPCR activation.
PubMed: 37905159
DOI: 10.1101/2023.10.16.562552