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Arthritis & Rheumatology (Hoboken, N.J.) Aug 2023To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis.
OBJECTIVE
To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis.
METHODS
In this study we investigated the role of IL-23 in osteoclast differentiation and activation using in vivo gene transfer techniques in wild-type and myeloid DNAX-activation protein 12-associating lectin-1 (MDL-1)-deficient mice, and by performing in vitro and in vivo osteoclastogenesis assays using spectral flow cytometry, micro-computed tomography analysis, Western blotting, and immunoprecipitation.
RESULTS
Herein, we show that IL-23 induces the expansion of a myeloid osteoclast precursor population and supports osteoclastogenesis and bone resorption in inflammatory arthritis. Genetic ablation of C-type lectin domain family member 5A, also known as MDL-1, prevents the induction of osteoclast precursors by IL-23 that is associated with bone destruction, as commonly observed in inflammatory arthritis. Moreover, osteoclasts derived from the bone marrow of MDL-1-deficient mice showed impaired osteoclastogenesis, and MDL-1 mice had increased bone mineral density.
CONCLUSION
Our data show that IL-23 signaling regulates the availability of osteoclast precursors in inflammatory arthritis that could be effectively targeted for the treatment of inflammatory bone loss in inflammatory arthritis.
Topics: Mice; Animals; Osteoclasts; Osteogenesis; Interleukin-23; X-Ray Microtomography; Bone Resorption; Arthritis; Cell Differentiation; RANK Ligand
PubMed: 36787107
DOI: 10.1002/art.42478 -
Synthetic and Systems Biotechnology Dec 2023The microbial synthesis of paclitaxel is attractive for its short-cycle, cost-effectiveness, and sustainability. However, low paclitaxel productivity, depleted capacity... (Review)
Review
The microbial synthesis of paclitaxel is attractive for its short-cycle, cost-effectiveness, and sustainability. However, low paclitaxel productivity, depleted capacity during subculture and storage, and unclear biosynthesis mechanisms restrain industrial microbial synthesis. Along with the isolation of various paclitaxel-producing microorganisms and the development of versatile molecular tools, tremendous promises for microbial paclitaxel synthesis have become increasingly prominent. In this review, we summarize the progress of microbial synthesis of paclitaxel in recent years, focusing on paclitaxel-producing endophytes and representative engineering microorganism hosts that were used as chassis for paclitaxel precursor synthesis. Numerous wide-type microbes can manufacture paclitaxel, and fermentation process optimization and strain improvement can greatly enhance the productivity. Engineered microbes can efficiently synthesize precursors of paclitaxel by introducing exogenous synthetic pathway. Mining paclitaxel synthetic pathways and genetic manipulation of endophytes will accelerate the construction of microbial cell factories, indefinitely contributing to paclitaxel mass production by microbes. This review emphasizes the potential and provides solutions for efficient microbial paclitaxel mass production.
PubMed: 37954482
DOI: 10.1016/j.synbio.2023.10.002 -
Frontiers in Plant Science 2023Phytosulfokines (PSKs) are a class of disulfated pentapeptides and are regarded as plant peptide hormones. PSK-α, -γ, -δ, and -ϵ are four bioactive PSKs that are... (Review)
Review
Phytosulfokines (PSKs) are a class of disulfated pentapeptides and are regarded as plant peptide hormones. PSK-α, -γ, -δ, and -ϵ are four bioactive PSKs that are reported to have roles in plant growth, development, and immunity. In this review, we summarize recent advances in PSK biosynthesis, signaling, and function. PSKs are encoded by precursor genes that are widespread in higher plants. PSKs maturation from these precursors requires a sulfation step, which is catalyzed by a tyrosylprotein sulfotransferase, as well as proteolytic cleavage by subtilisin serine proteases. PSK signaling is mediated by plasma membrane-localized receptors PSKRs that belong to the leucine-rich repeat receptor-like kinase family. Moreover, multiple biological functions can be attributed to PSKs, including promoting cell division and cell growth, regulating plant reproduction, inducing somatic embryogenesis, enhancing legume nodulation, and regulating plant resistance to biotic and abiotic stress. Finally, we propose several research directions in this field. This review provides important insights into PSKs that will facilitate biotechnological development and PSK application in agriculture.
PubMed: 38250441
DOI: 10.3389/fpls.2023.1326964 -
Communications Biology Nov 2023The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis....
The vast majority of Parkinson's disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson's disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.
Topics: Humans; Parkinson Disease; NAD; Neural Stem Cells; Mitochondria; Dopaminergic Neurons
PubMed: 37985891
DOI: 10.1038/s42003-023-05548-w -
Proceedings of the National Academy of... Oct 2023Precursor tRNAs are transcribed with flanking and intervening sequences known to be processed by specific ribonucleases. Here, we show that transcription complexes of...
Precursor tRNAs are transcribed with flanking and intervening sequences known to be processed by specific ribonucleases. Here, we show that transcription complexes of RNA polymerase III assembled on tRNA genes comprise RNase P that cleaves precursor tRNA and subsequently degrades the excised 5' leader. Degradation is based on a 3'-5' exoribonucleolytic activity carried out by the protein subunit Rpp14, as determined by biochemical and reverse genetic analyses. Neither reconstituted nor purified RNase P displays this magnesium ion-dependent, processive exoribonucleolytic activity. Markedly, knockdown of Rpp14 by RNA interference leads to a wide-ranging inhibition of cleavage of flanking and intervening sequences of various precursor tRNAs in extracts and cells. This study reveals that RNase P controls tRNA splicing complex and RNase Z for ordered maturation of nascent precursor tRNAs by transcription complexes.
Topics: Humans; Ribonuclease P; RNA Precursors; Endoribonucleases; RNA, Transfer; Ribonucleases; RNA Splicing
PubMed: 37831743
DOI: 10.1073/pnas.2307185120 -
ACS Applied Materials & Interfaces Aug 2023The maskless and chemical-free conversion and patterning of synthetic polymer precursors into laser-induced graphene (LIG) via laser-induced pyrolysis is a relatively... (Review)
Review
The maskless and chemical-free conversion and patterning of synthetic polymer precursors into laser-induced graphene (LIG) via laser-induced pyrolysis is a relatively new but growing field. Bioderived precursors from lignocellulosic materials can also be converted to LIG, opening a path to sustainable and environmentally friendly applications. This review is designed as a starting point for researchers who are not familiar with LIG and/or who wish to switch to sustainable bioderived precursors for their applications. Bioderived precursors are described, and their performances (mainly crystallinity and sheet resistance of the obtained LIG) are compared. The three main fields of application are reviewed: supercapacitors and electrochemical and physical sensors. The key advantages and disadvantages of each precursor for each application are discussed and compared to those of a benchmark of polymer-derived LIG. LIG from bioderived precursors can match, or even outperform, its synthetic analogue and represents a viable and sometimes better alternative, also considering its low cost and biodegradability.
PubMed: 37471123
DOI: 10.1021/acsami.3c07687 -
Cell Reports Dec 2023Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are...
Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4 T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.
Topics: Animals; Mice; Argonaute Proteins; Imidazoline Receptors; Mammals; MicroRNAs; RNA Interference; RNA Precursors; RNA Splicing; RNA, Messenger
PubMed: 38096048
DOI: 10.1016/j.celrep.2023.113515 -
Signal Transduction and Targeted Therapy Jan 2024The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with...
The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.
Topics: Female; Humans; Animals; Mice; Valproic Acid; Antagomirs; In Situ Hybridization, Fluorescence; Extracellular Vesicles; MicroRNAs
PubMed: 38246920
DOI: 10.1038/s41392-023-01726-8 -
Frontiers in Cellular and Infection... 2023The polysaccharide capsule of plays a major role in virulence, adherence to epithelial cells, and overall survival of the bacterium in the human host. Galactose,...
BACKGROUND
The polysaccharide capsule of plays a major role in virulence, adherence to epithelial cells, and overall survival of the bacterium in the human host. Galactose, mannose, and N-acetylglucosamine (GlcNAc) are likely to be relevant for metabolization in the nasopharynx, while glucose is the primary carbon source in the blood. In this study, we aim to further the understanding of the influence of carbon sources on pneumococcal growth, capsule biosynthesis, and subsequent adherence potential.
METHODS
We tested the growth behavior of clinical wild-type and capsule knockout strains, using galactose, GlcNAc, mannose, and glucose as carbon source for growth. We measured capsule thickness and quantified capsule precursors by fluorescein isothiocyanate (FITC)-dextran exclusion assays and P-nuclear magnetic resonance measurements, respectively. We also performed epithelial adherence assays using Detroit 562 cells and performed a transcriptome analysis (RNA sequencing).
RESULTS
We observed a reduced growth in galactose, mannose, and GlcNAc compared to growth in glucose and found capsular size reductions in mannose and GlcNAc compared to galactose and glucose. Additionally, capsular precursor measurements of uridine diphosphate-(UDP)-glucose and UDP-galactose showed less accumulation of precursors in GlcNAc or mannose than in glucose and galactose, indicating a possible link with the received capsular thickness measurements. Epithelial adherence assays showed an increase in adherence potential for a pneumococcal strain, when grown in mannose compared to glucose. Finally, transcriptome analysis of four clinical isolates revealed not only strain specific but also common carbon source-specific gene expression.
CONCLUSION
Our findings may indicate a careful adaption of the lifestyle of according to the monosaccharides encountered in the respective human niche.
Topics: Humans; Streptococcus pneumoniae; Galactose; Carbon; Mannose; Glucose; Uridine Diphosphate; Bacterial Capsules
PubMed: 38094742
DOI: 10.3389/fcimb.2023.1279119 -
Antioxidants & Redox Signaling Dec 2023Nicotinamide adenine dinucleotide (NAD) is an important molecule synthesized from tryptophan or vitamin B3 and involved in numerous cellular reactions. NAD deficiency... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) is an important molecule synthesized from tryptophan or vitamin B3 and involved in numerous cellular reactions. NAD deficiency during pregnancy causes congenital NAD deficiency disorder (CNDD) characterized by multiple congenital malformations and/or miscarriage. Studies in genetically engineered mice replicating mutations found in human patient cases show that CNDD can be prevented by dietary supplements. A growing number of patient reports show that biallelic loss-of-function of genes involved in NAD synthesis (, , ) cause CNDD. Other factors that limit the availability of NAD precursors, for example, limited dietary precursor supply or absorption, can cause or contribute to NAD deficiency and result in CNDD in mice. Molecular flux experiments allow quantitative understanding of NAD precursor concentrations in the circulation and their usage by different cells. Studies of NAD-consuming enzymes and contributors to NAD homeostasis help better understand how perturbed NAD levels are implicated in various diseases and adverse pregnancy outcomes. NAD deficiency is one of the many known causes of adverse pregnancy outcomes, but its prevalence in the human population and among pregnant women is unknown. Since NAD is involved in hundreds of diverse cellular reactions, determining how NAD deficiency disrupts embryogenesis is an important challenge. Furthering our understanding of the molecular fluxes between the maternal and embryonic circulation during pregnancy, the NAD-dependent pathways active in the developing embryo, and the molecular mechanisms by which NAD deficiency causes adverse pregnancy outcomes will provide direction for future prevention strategies. 39, 1108-1132.
Topics: Humans; Female; Pregnancy; Animals; Mice; NAD; Dietary Supplements; Oxidation-Reduction; Mutation; Mammals
PubMed: 37300479
DOI: 10.1089/ars.2023.0349