-
Journal of Orthopaedic Surgery and... Sep 2023Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a...
BACKGROUND
Spondyloarthritis (SpA) is a group of multifactorial bone diseases influenced by genetic factors, the environment and lifestyle. However, current studies have found a limited number of SpA-related genes, and the genetic and pathogenic mechanisms of SpA are still unclear.
METHODS
A tissue-specific transcriptome-wide association study (TWAS) of SpA was performed using GWAS (including 3966 SpA patients and 448,298 controls) summary data and gene expression weights of whole blood and skeletal muscle. The SpA-associated genes identified by TWAS were further compared with the differentially expressed genes (DEGs) identified in the SpA gene expression profile acquired from the Gene Expression Omnibus database (GEO, GSE58667). Finally, functional enrichment and annotation analyses of the identified genes were performed.
RESULTS
The TWAS detected 499 suggestive genes associated with SpA in whole blood and skeletal muscle, such as CTNNAL1 (P = 3.04 × 10, P = 9.58 × 10). The gene expression profile of SpA identified 20 candidate genes that overlapped in the TWAS data, such as MCM4 (P = 1.32 × 10, P = 2.75 × 10) and KIAA1109 (P = 3.71 × 10, P = 4.67 × 10). Enrichment analysis of the genes identified by TWAS identified 93 significant GO terms and 33 KEGG pathways, such as mitochondrion organization (GO: 0007005) and axon guidance (hsa04360).
CONCLUSION
We identified multiple candidate genes that were genetically related to SpA. Our study may provide novel clues regarding the genetic mechanism, diagnosis, and treatment of SpA.
Topics: Humans; Transcriptome; Bone Diseases; Databases, Factual; Life Style; Spondylarthritis
PubMed: 37667381
DOI: 10.1186/s13018-023-04029-4 -
Metallomics : Integrated Biometal... Jun 2024Ferric-tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously...
Ferric-tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously shown that FTs could activate axon guidance pathways and cellular clearance functioning in neuronal cell lines. Herein, we further investigated whether FTs could activate the two coordinated neuronal functions of axon guidance and synaptic function in rat brains and neuronal cell lines. A single intravenous injection of safe dose of FTs has been shown to activate a protein expression of axon attractant Netrin-1 and neurotransmitter receptor GABRA4 in the cerebral cortexes of male Wistar rats. According to RNA-seq with targeted analysis, axon guidance and synapses have been enriched and Ephrin membered genes have been identified as coordinating a network of genes for such processes. In vitro, as expected, FTs are also found to activate axon guidance markers and promote neuronal tubes in neuronal cell lines. At the same time, presynaptic markers (synaptophysin), post-synaptic markers (synapsin), and GABRA4 neurotransmitter receptors have been found to be activated by FTs. Interestingly, synaptophysin has been found to localize along the promoted neuronal tubes, suggesting that enhanced axon guidance is associated with the formation and transportation of pre-synaptic vesicles. Preliminarily, repeated injection of FTs into adult rats every 3 days for 10 times could enhance an expression of synaptophysin in cerebral cortex, as compared to control rat. This work demonstrates that FTs can be used for activating brain function associated with axon guidance and synaptic function.
PubMed: 38936837
DOI: 10.1093/mtomcs/mfae031 -
Proceedings of the National Academy of... Sep 2023Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential...
Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential for the plasticity and remodeling that underlie behavioral adaptations. Importantly, the mechanisms of actin assembly have been well-defined-including that it is driven by actin's polymerization into filaments (F-actin) and then often bundling by crosslinking proteins into stable higher-order structures. In contrast, it remains less clear how these stable bundled F-actin structures are rapidly disassembled. We now uncover mechanisms that rapidly and extensively disassemble bundled F-actin. Using biochemical, structural, and imaging assays with purified proteins, we show that F-actin bundled with one of the most prominent crosslinkers, fascin, is extensively disassembled by Mical, the F-actin disassembly enzyme. Furthermore, the product of this Mical effect, Mical-oxidized actin, is poorly bundled by fascin, thereby further amplifying Mical's disassembly effects on bundled F-actin. Moreover, another critical F-actin regulator, cofilin, also affects fascin-bundled filaments, but we find herein that it synergizes with Mical to dramatically amplify its disassembly of bundled F-actin compared to the sum of their individual effects. Genetic and high-resolution cellular assays reveal that Mical also counteracts crosslinking proteins/bundled F-actin in vivo to control cellular extension, axon guidance, and Semaphorin/Plexin cell-cell repulsion. Yet, our results also support the idea that fascin-bundling serves to dampen Mical's F-actin disassembly in vitro and in vivo-and that physiologically relevant cellular remodeling requires a fine-tuned interplay between the factors that build bundled F-actin networks and those that disassemble them.
Topics: Actins; Actin Depolymerizing Factors; Actin Cytoskeleton; Cytoskeleton; Axon Guidance
PubMed: 37725655
DOI: 10.1073/pnas.2309955120 -
International Journal of General... 2023We aimed to explore the expressions of peptidoglycan recognition protein 1 (PGLYRP-1), neuron towards axon guidance factor-1 (Netrin-1) and miR-142-3p and their...
PURPOSE
We aimed to explore the expressions of peptidoglycan recognition protein 1 (PGLYRP-1), neuron towards axon guidance factor-1 (Netrin-1) and miR-142-3p and their correlations in patients with rheumatoid arthritis.
PATIENTS AND METHODS
Sixty patients with rheumatoid arthritis treated from January 2022 to January 2023 were enrolled as a rheumatoid group, 30 patients with osteoarthritis were selected as an osteoarthritis group, and 30 healthy volunteers were recruited as a control group. The enzyme-linked immunosorbent assay, Western blotting and reverse transcriptase-polymerase chain reaction were employed to measure the expressions of PGLYRP-1, Netrin-1 and miR-142-3p, respectively. The correlations among PGLYRP-1, Netrin-1 and miR-142-3p expressions in patients with rheumatoid arthritis were analyzed.
RESULTS
In patients with rheumatoid arthritis, PGLYRP-1 expression was negatively correlated with Netrin-1 expression (r=-0.570, P=0.001) but positively correlated with miR-142-3p expression (r=0.599, P=0.001), and a negative correlation was found between Netrin-1 and miR-142-3p expressions (r=-0.468, P=0.001). The combined detection of PGLYRP-1, Netrin-1 and miR-142-3p was more sensitive and less specific for predicting the prognosis of patients with rheumatoid arthritis than the measurement of a single marker (P<0.05).
CONCLUSION
The combined measurement of PGLYRP-1, Netrin-1 and miR-142-3p has a predictive value for the prognosis of patients with rheumatoid arthritis.
PubMed: 37601805
DOI: 10.2147/IJGM.S418396 -
Biomaterials Research Oct 2023Neural stem cells (NSCs) derived from the embryonic spinal cord are excellent candidates for the cellular regeneration of lost neural cells after spinal cord injury...
BACKGROUND
Neural stem cells (NSCs) derived from the embryonic spinal cord are excellent candidates for the cellular regeneration of lost neural cells after spinal cord injury (SCI). Semaphorin 3 A (Sema3A) is well known as being implicated in the major axon guidance of the growth cone as a repulsive function during the development of the central nervous system, yet its function in NSC transplantation therapy for SCI has not been investigated. Here, we report for the first time that embryonic spinal cord-derived NSCs significantly express Sema3A in the SCI environment, potentially facilitating inhibition of cell proliferation after transplantation.
METHODS
siRNA-Sema3A was conjugated with poly-l-lysin-coated gold nanoparticles (AuNPs) through a charge interaction process. NSCs were isolated from embryonic spinal cords of rats. Then, the cells were embedded into a dual-degradable hydrogel with the siRNA- Sema3A loaded-AuNPs and transplanted after complete SCI in rats.
RESULTS
The knockdown of Sema3A by delivering siRNA nanoparticles via dual-degradable hydrogels led to a significant increase in cell survival and neuronal differentiation of the transplanted NSCs after SCI. Of note, the knockdown of Sema3A increased the synaptic connectivity of transplanted NSC in the injured spinal cord. Moreover, extracellular matrix molecule and functional recovery were significantly improved in Sema3A-inhibited rats compared to those in rats with only NSCs transplanted.
CONCLUSIONS
These findings demonstrate the important role of Sema3A in NSC transplantation therapy, which may be considered as a future cell transplantation therapy for SCI cases.
PubMed: 37840145
DOI: 10.1186/s40824-023-00434-2 -
BioRxiv : the Preprint Server For... Apr 2024Recent studies in vertebrates and have reshaped models of how the axon guidance cue UNC-6/Netrin functions in dorsal-ventral axon guidance, which was traditionally...
Recent studies in vertebrates and have reshaped models of how the axon guidance cue UNC-6/Netrin functions in dorsal-ventral axon guidance, which was traditionally thought to form a ventral-to-dorsal concentration gradient that was actively sensed by growing axons. In the vertebrate spinal cord, floorplate Netrin1 was shown to be largely dispensable for ventral commissural growth. Rather, short range interactions with Netrin1 on the ventricular zone radial glial stem cells was shown to guide ventral commissural axon growth. In , analysis of dorsally-migrating growth cones during outgrowth has shown that growth cone polarity of filopodial extension is separable from the extent of growth cone protrusion. Growth cones are first polarized by UNC-6/Netrin, and subsequent regulation of protrusion by UNC-6/Netrin is based on this earlier-established polarity (the Polarity/Protrusion model). In both cases, short-range or even haptotactic mechanisms are invoked: in vertebrate spinal cord, interactions of growth cones with radial glia expressing Netrin-1; and in a potential close-range interaction that polarizes the growth cone. To explore potential short-range and long-range functions of UNC-6/Netrin, a potentially membrane-anchored transmembrane UNC-6 (UNC-6(TM)) was generated by genome editing. was hypomorphic for dorsal VD/DD axon pathfinding, indicating that it retained some function. Polarity of VD growth cone filopodial protrusion was initially established in , but was lost as the growth cones migrated away from the source in the ventral nerve cord. In contrast, ventral guidance of the AVM and PVM axons was equally severe in and . Together, these results suggest that retains short-range functions but lacks long-range functions. Finally, ectopic expression from non-ventral sources could rescue dorsal and ventral guidance defects in and . Thus, a ventral directional source of UNC-6 was not required for dorsal-ventral axon guidance, and UNC-6 can act as a permissive, not instructive, cue for dorsal-ventral axon guidance. Possibly, UNC-6 is a permissive signal that activates cell-intrinsic polarity; or UNC-6 acts with another signal that is required in a directional manner. In either case, the role of UNC-6 is to polarize the pro-protrusive activity of UNC-40/DCC in the direction of outgrowth.
PubMed: 38712249
DOI: 10.1101/2024.04.23.590737 -
The Journal of Pathology Feb 2024Neuropilin-2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in...
Neuropilin-2 (NRP2) is a multifunctional protein engaged in the regulation of angiogenesis, lymphangiogenesis, axon guidance, and tumor metastasis, but its function in colitis remains unclear. Here, we found that NRP2 was an inflammation-sensing protein rapidly and dramatically induced in myeloid cells, especially in macrophages, under inflammatory contexts. NRP2 deficiency in myeloid cells exacerbated dextran sulfate sodium salt-induced experimental colitis by promoting polarization of M1 macrophages and colon injury. Mechanistically, NRP2 could be induced via NF-κB activation by TNF-α in macrophages, but exerted an inhibitory effect on NF-κB signaling, forming a negative feedback loop with NF-κB to sense and alleviate inflammation. Deletion of NRP2 in macrophages broke this negative feedback circuit, leading to NF-κB overactivation, inflammatory exacerbation, and more severe colitis. Collectively, these findings reveal inflammation restriction as a role for NRP2 in macrophages under inflammation contexts and suggest that NRP2 in macrophages may relieve inflammation in inflammatory bowel disease. © 2023 The Pathological Society of Great Britain and Ireland.
Topics: Humans; Animals; Mice; NF-kappa B; Neuropilin-2; Colitis; Inflammation; Macrophages; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37946610
DOI: 10.1002/path.6221 -
American Journal of Cancer Research 2023Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC), and they are associated with a poor prognosis. Axon guidance...
Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC), and they are associated with a poor prognosis. Axon guidance factor semaphorin 3A (SEMA3A) is upregulated in PDAC. However, it remains unclear whether cancer-derived SEMA3A influences nerve innervation and pancreatic tumorigenesis. analyses were performed using PROGgene and NetworkAnalyst to clarify the importance of SEMA3A and its receptors, plexin A1 (PLXNA1) and neuropilin 2 (NRP2), in pancreatic cancer. assays, including migration, neurite outgrowth, and 3D recruitment, were performed to study the effects of SEMA3A on neuronal behaviors. Additionally, an orthotopic animal study using C57BL/6 mice was performed to validate the findings. Expression of SEMA3A and its receptors predicted worse prognosis for PDAC. Cancer-derived SEMA3A promoted neural migration, neurite outgrowth, and neural recruitment. Furthermore, SEMA3A-induced effects depended on PLXNA1, NRP2, and MAPK activation. Trametinib, an approved MAPK kinase (MEK) inhibitor, counteracted SEMA3A-enhanced neuronal activity . Inhibition of SEMA3A by shRNA in pancreatic cancer cells resulted in decreased neural recruitment, tumor growth, and dissemination . Our results suggested that cancer-secreted SEMA3A plays an important role in promoting neo-neurogenesis and progression of PDAC.
PubMed: 37693128
DOI: No ID Found -
Journal of Neuroscience Research Jan 2024The altered activity generated by corneal neuronal injury can result in morphological and physiological changes in the architecture of synaptic connections in the... (Review)
Review
The altered activity generated by corneal neuronal injury can result in morphological and physiological changes in the architecture of synaptic connections in the nervous system. These changes can alter the sensitivity of neurons (both second-order and higher-order projection) projecting pain signals. A complex process involving different cell types, molecules, nerves, dendritic cells, neurokines, neuropeptides, and axon guidance molecules causes a high level of sensory rearrangement, which is germane to all the phases in the pathomechanism of corneal neuropathic pain. Immune cells migrating to the region of nerve injury assist in pain generation by secreting neurokines that ensure nerve depolarization. Furthermore, excitability in the central pain pathway is perpetuated by local activation of microglia in the trigeminal ganglion and alterations of the descending inhibitory modulation for corneal pain arriving from central nervous system. Corneal neuropathic pain may be facilitated by dysfunctional structures in the central somatosensory nervous system due to a lesion, altered synaptogenesis, or genetic abnormality. Understanding these important pathways will provide novel therapeutic insight.
Topics: Humans; Neuralgia; Cornea; Central Nervous System; Neurons; Axon Guidance
PubMed: 38284865
DOI: 10.1002/jnr.25285 -
Cancer Biology & Therapy Dec 2023Acute myeloid leukemia (AML) is a hematological malignancy that commonly occurs in children. The prognosis of pediatric AML is relatively poor, thus threatening the...
Acute myeloid leukemia (AML) is a hematological malignancy that commonly occurs in children. The prognosis of pediatric AML is relatively poor, thus threatening the patient's survival. The aberrant expression of the axon guidance factor, netrin-1, is observed in various types of malignancies, and it participates in the proliferation and apoptosis of tumor cells. Herein, we aimed to explore the role of netrin-1 in AML cells. Netrin-1 is highly expressed in AML patients. Proliferation and anti-apoptosis were observed in AML cells treated with netrin-1. The interaction between netrin-1 and Unc-5 netrin receptor B (UNC5B) was detected through coimmunoprecipitation, and UNC5B ribonucleic acid interference restrained the influence of netrin-1 on the AML cells. The phosphorylation of focal adhesion kinase-protein kinase B (FAK-Akt) was upregulated in AML cells treated with netrin-1. Both FAK and Akt inhibitors abrogated the effects of netrin-1 on the proliferation and apoptosis of AML cells. In conclusion, netrin-1 could promote the growth and reduce the apoptosis of AML cells in a concentration-dependent manner, and that these effects were mediated by activating the FAK-Akt signaling pathway via the UNC5B.
Topics: Child; Humans; Focal Adhesion Protein-Tyrosine Kinases; Leukemia, Myeloid, Acute; Netrin Receptors; Netrin-1; Proto-Oncogene Proteins c-akt
PubMed: 37038247
DOI: 10.1080/15384047.2023.2200705