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Journal of Clinical Periodontology Jul 2024To identify an optimized strategy for the large-scale production of nanovesicles (NVs) that preserve the biological properties of exosomes (EXOs) for use in periodontal...
AIM
To identify an optimized strategy for the large-scale production of nanovesicles (NVs) that preserve the biological properties of exosomes (EXOs) for use in periodontal regeneration.
MATERIALS AND METHODS
NVs from dental follicle stem cells (DFSCs) were prepared through extrusion, and EXOs from DFSCs were isolated. The yield of both extruded NVs (eNVs) and EXOs were quantified through protein concentration and particle number analyses. Their pro-migration, pro-proliferation and pro-osteogenesis capacities were compared subsequently in vitro. Additionally, proteomics analysis was conducted. To further evaluate the periodontal regeneration potential of eNVs and EXOs, they were incorporated into collagen sponges and transplanted into periodontal defects in rats. In vivo imaging and H&E staining were utilized to verify their biodistribution and safety. Micro-Computed Tomography analysis and histological staining were performed to examine the regeneration of periodontal tissues.
RESULTS
The yield of eNVs was nearly 40 times higher than that of EXOs. Interestingly, in vitro experiments indicated that the pro-migration and pro-proliferation abilities of eNVs were superior, and the pro-osteogenesis potential was comparable to EXOs. More importantly, eNVs exhibited periodontal regenerative potential similar to that of EXOs.
CONCLUSIONS
Extrusion has proven to be an efficient method for generating numerous eNVs with the potential to replace EXOs in periodontal regeneration.
PubMed: 38951121
DOI: 10.1111/jcpe.14036 -
The Journal of Rheumatology Jul 2024Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated... (Review)
Review
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly , in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
Topics: Humans; Arthritis, Rheumatoid; Gene-Environment Interaction; Indians, North American; Animals; Anti-Citrullinated Protein Antibodies; Biomarkers
PubMed: 38950968
DOI: 10.3899/jrheum.2024-0369_dunlop-dottridge -
International Journal of Gynecological... Jun 2024Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique... (Review)
Review
Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway (, , and ), and in genes related to the MAPK pathway (, and ). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include , and but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research.
PubMed: 38950921
DOI: 10.1136/ijgc-2024-005305 -
Cellular Signalling Jun 2024Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical...
Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical management. In this study, we investigated the underlying mechanism driving the hyperinflammatory response in gingival epithelial cells (GECs) of DP patients. Our findings indicate that lysosomal dysfunction under high glucose conditions leads to the blockage of autophagy flux, exacerbating inflammatory response in GECs. Single-cell RNA sequencing and immunohistochemistry analyses of clinical gingival epithelia revealed dysregulation in the lysosome pathway characterized by reduced levels of lysosome-associated membrane glycoprotein 2 (LAMP2) and V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C) in subjects with DP. In vitro stimulation of human gingival epithelial cells (HGECs) with a hyperglycemic microenvironment showed elevated release of proinflammatory cytokines, compromised lysosomal acidity and blocked autophagy. Moreover, HGECs with deficiency in ATP6V0C demonstrated impaired autophagy and heightened inflammatory response, mirroring the effects of high glucose stimulation. Proteomic analysis of acetylation modifications identified altered acetylation levels in 28 autophagy-lysosome pathway-related proteins and 37 sites in HGECs subjected to high glucose stimulation or siATP6V0C. Overall, our finding highlights the pivotal role of lysosome impairment in autophagy obstruction in DP and suggests a potential impact of altered acetylation of relevant proteins on the interplay between lysosome dysfunction and autophagy blockage. These insights may pave the way for the development of effective therapeutic strategies against DP.
PubMed: 38950874
DOI: 10.1016/j.cellsig.2024.111273 -
The Journal of Biological Chemistry Jun 2024Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment... (Review)
Review
Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment and biological processes. The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed endocytic receptor that regulates cellular events by modulating the levels of numerous extracellular molecules via rapid endocytic removal. LRP1 also participates in signalling pathways through this modulation as well as in the interaction with membrane receptors and cytoplasmic adaptor proteins. LRP1 single nucleotide polymorphisms are associated with several diseases and conditions such as migraines, aortic aneurysms, cardiopulmonary dysfunction, corneal clouding, and bone dysmorphology and mineral density. Studies using Lrp1 knockout mice revealed a critical, non-redundant and tissue-specific role of LRP1 in regulating various physiological events. However, exactly how LRP1 functions to regulate so many distinct and specific processes is still not fully clear. Our recent proteomics studies have identified more than 300 secreted proteins that either directly interact with LRP1 or are modulated by LRP1 in various tissues. This review will highlight the remarkable ability of this receptor to regulate secreted molecules in a tissue-specific manner and discuss potential mechanisms underpinning such specificity. Uncovering the depth of these "hidden" specific interactions modulated by LRP1 will provide novel insights into a dynamic and complex extracellular environment that is involved in diverse biological and pathological processes.
PubMed: 38950861
DOI: 10.1016/j.jbc.2024.107521 -
European Journal of Pharmacology Jun 2024With a global towering prevalence of index acute myocardial infarction (nonrecurrent MI, NR-MI), a high incidence of recurrent MI (R-MI) has emerged in recent decades....
With a global towering prevalence of index acute myocardial infarction (nonrecurrent MI, NR-MI), a high incidence of recurrent MI (R-MI) has emerged in recent decades. Despite the extensive occurrence, the promising predictors of R-MI have been elusive within the cohort of survivors. This study investigates and validates the involvement of distinct gene expressions in R-MI and NR-MI. Bioinformatics tools were used to identify DEGs from the GEO dataset, functional annotation, pathway enrichment analysis, and the PPI network analysis to find hub genes. The validation of proposed genes was conceded by qRT-PCR and Western Blot analysis in experimentally induced NR-MI and R-MI models on a temporal basis. The temporal findings based on RT-PCR consequences reveal a significant and constant upregulation of the UBE2N in the NR-MI model out of the proposed three DEGs (UBE2N, UBB, and TMEM189), while no expression was reported in the R-MI model. Additionally, the proteomics study proposed five DEGs (IL2RB, NKG7, GZMH, CXCR6, and GZMK) for the R-MI model since IL2RB was spotted for significant and persistent downregulation with different time points. Further, Western Blot analysis validated these target genes' expressions temporally. I/R-induced NR-MI and R-MI models were confirmed by the biochemical parameters (CKMB, LDH, cTnI, serum nitrite/nitrate concentration, and inflammatory cytokines) and histological assessments of myocardial tissue. These results underscore the importance of understanding genetic mechanisms underlying MI and highlight the potential of UBE2N and IL2RB as biomarkers for non-recurrent and recurrent MI, respectively.
PubMed: 38950836
DOI: 10.1016/j.ejphar.2024.176795 -
Chemosphere Jun 2024Marine ecosystems are under escalating threats from myriad environmental stressors, necessitating a deeper understanding of their impact on biodiversity and the health...
Marine ecosystems are under escalating threats from myriad environmental stressors, necessitating a deeper understanding of their impact on biodiversity and the health of sentinel organisms. In this study, we carried out a spatiotemporal multi-omic analysis of liquid biopsies collected from mussels (Mytilus spp.) in marine ecosystems of a national park. We delved into the epigenomic, transcriptomic, glycomic, proteomic, and microbiomic profiles to unravel the intricate interplay between ecosystem biodiversity and mussels' biological response to their environments. Our analysis revealed temporal fluctuations in the alpha diversity of the circulating microbiome associated with human activities. Analysis of the hemolymphatic circulating cell-free DNA (ccfDNA) provided information on the biodiversity and the presence of potential pathogens. Epigenomic analysis revealed widespread hypomethylation sites within the mitochondrial (mtDNA). Comparative transcriptomic and glycomic analyses highlighted differences in metabolic pathways and genes associated with immune and wound healing functions. This study demonstrates the potential of multi-omic analysis of liquid biopsy in sentinel to provide a holistic view of human activities' environmental impacts on marine coastal ecosystems. Overall, this approach has the potential to enhance the effectiveness and efficiency of various conservation efforts, leading to more informed decision-making and better outcomes for biodiversity and ecosystem conservation.
PubMed: 38950751
DOI: 10.1016/j.chemosphere.2024.142714 -
Toxicon : Official Journal of the... Jun 2024Snakebite envenomation has been a long-standing global issue that is difficult to treat, largely owing to the flawed nature of current immunoglobulin-based antivenom... (Review)
Review
Snakebite envenomation has been a long-standing global issue that is difficult to treat, largely owing to the flawed nature of current immunoglobulin-based antivenom therapy and the complexity of snake venoms as sophisticated mixtures of bioactive proteins and peptides. Comprehensive characterisation of venom compositions is essential to better understanding snake venom toxicity and inform effective and rationally designed antivenoms. Additionally, a greater understanding of snake venom composition will likely unearth novel biologically active proteins and peptides that have promising therapeutic or biotechnological applications. While a bottom-up proteomic workflow has been the main approach for cataloguing snake venom compositions at the toxin family level, it is unable to capture snake venom heterogeneity in the form of protein isoforms and higher-order protein interactions that are important in driving venom toxicity but remain underexplored. This review aims to highlight the importance of understanding snake venom heterogeneity beyond the primary sequence, in the form of post-translational modifications that give rise to different proteoforms and the myriad of higher-order protein complexes in snake venoms. We focus on current top-down proteomics workflows to identify snake venom proteoforms and further discuss alternative or novel separation, instrumentation, and data processing strategies that may improve proteoform identification. The current higher-order structural characterisation techniques implemented for snake venom proteins are also discussed; we emphasise the need for complementary and higher resolution structural bioanalytical techniques such as mass spectrometry-based approaches, X-ray crystallography and cryogenic electron microscopy, to elucidate poorly characterised tertiary and quaternary protein structures. We envisage that the expansion of the snake venom characterisation "toolbox" with top-down proteomics and high-resolution protein structure determination techniques will be pivotal in advancing structural understanding of snake venoms towards the development of improved therapeutic and biotechnology applications.
PubMed: 38950738
DOI: 10.1016/j.toxicon.2024.107841 -
Journal of Proteomics Jun 2024The aim of this study was to explore potentially novel plasma protein biomarkers for lung adenocarcinoma (LUAD). A plasma proteomics analysis was carried and candidate...
Plasma GPI and PGD are associated with vascular normalization and may serve as novel prognostic biomarkers for lung adenocarcinoma: Multi-omics and multi-dimensional analysis.
The aim of this study was to explore potentially novel plasma protein biomarkers for lung adenocarcinoma (LUAD). A plasma proteomics analysis was carried and candidate protein biomarkers were validated in 102 LUAD cases and 102 matched healthy controls. The same LUAD tumor tissues were detected to explore the correlation between the expression of candidate proteins in tissues and plasma and vascular normalization. A LUAD active metastasis mice model was constructed to explore the role of candidate proteins for lung metastasis. GPI and PGD were verified to be upregulated in plasma from LUAD patients, and the expression of GPI in tumor tissue was positively correlated with the expression of GPI in plasma and negatively correlated with the normalization of tumor blood vessels. Meanwhile, a negative correlation between the expression of GPI and PGD in plasma and tumor vascular normalization was discovered. In the LUAD active metastasis model, the lowest levels of vascular normalization and the highest expression of GPI and PGD were found in mice with lung metastases. This study found that GPI and PGD may be potential plasma biomarkers for LUAD, and monitoring those may infer the risk of metastasis and malignancy of the tumor. SIGNIFICANT: We identified GPI and PGD as potential novel diagnostic and prognostic biomarkers for LUAD. PGD and GPI can be used as diagnostic biomarkers in combination with other available strategies to assist in the screening and diagnosis of LUAD, and as prognostic biomarkers aid in predict the risk of tumor metastasis and malignancy in patients with LUAD.
PubMed: 38950696
DOI: 10.1016/j.jprot.2024.105247 -
Proceedings of the National Academy of... Jul 2024-methyladenosine (mA) is a fundamentally important RNA modification for gene regulation, whose function is achieved through mA readers. However, whether and how mA...
-methyladenosine (mA) is a fundamentally important RNA modification for gene regulation, whose function is achieved through mA readers. However, whether and how mA readers play regulatory roles during fruit ripening and quality formation remains unclear. Here, we characterized SlYTH2 as a tomato mA reader protein and profiled the binding sites of SlYTH2 at the transcriptome-wide level. SlYTH2 undergoes liquid-liquid phase separation and promotes RNA-protein condensate formation. The target mRNAs of SlYTH2, namely mA-modified and associated with volatile synthesis, are enriched in SlYTH2-induced condensates. Through polysome profiling assays and proteomic analysis, we demonstrate that knockout of expedites the translation process of and , resulting in augmented production of aroma-associated volatiles. This aroma enrichment significantly increased consumer preferences for CRISPR-edited fruit over wild type. These findings shed light on the underlying mechanisms of mA in plant RNA metabolism and provided a promising strategy to generate fruits that are more attractive to consumers.
Topics: Solanum lycopersicum; Fruit; Adenosine; Gene Expression Regulation, Plant; Plant Proteins; Protein Biosynthesis; Odorants
PubMed: 38950372
DOI: 10.1073/pnas.2405100121