-
Research Square Apr 2024Human males and females show differences in the incidence of neutrophil-associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, and reactive...
BACKGROUND
Human males and females show differences in the incidence of neutrophil-associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, and reactive arthritis, and differences in neutrophil physiological responses such as a faster response to the chemorepellent SLIGKV. Little is known about the basis of sex-based differences in human neutrophils.
METHODS
Starting with human neutrophils from healthy donors, we used RNA-seq to examine total mRNA profiles, mRNAs not associated with ribosomes and thus not being translated, mRNAs in monosomes, and mRNAs in polysomes and thus heavily translated. We used mass spectrometry systems to identify proteins and phosphoproteins.
RESULTS
There were sex-based differences in the translation of 24 mRNAs. There were 132 proteins with higher levels in male neutrophils; these tended to be associated with RNA regulation, ribosome, and phosphoinositide signaling pathways, whereas 30 proteins with higher levels in female neutrophils were associated with metabolic processes, proteosomes, and phosphatase regulatory proteins. Male neutrophils had increased phosphorylation of 32 proteins. After exposure to SLIGKV, male neutrophils showed a faster response in terms of protein phosphorylation compared to female neutrophils.
CONCLUSIONS
Male neutrophils have higher levels of proteins and higher phosphorylation of proteins associated with RNA processing and signaling pathways, while female neutrophils have higher levels of proteins associated with metabolism and proteolytic pathways. This suggests that male neutrophils might be more ready to adapt to a new environment, and female neutrophils might be more effective at responding to pathogens. This may contribute to the observed sex-based differences in neutrophil behavior and neutrophil-associated disease incidence and severity.
PubMed: 38746380
DOI: 10.21203/rs.3.rs-4284171/v1 -
Nature Communications May 2024Endocytosis requires a coordinated framework of molecular interactions that ultimately lead to the fission of nascent endocytic structures. How cytosolic proteins such...
Endocytosis requires a coordinated framework of molecular interactions that ultimately lead to the fission of nascent endocytic structures. How cytosolic proteins such as dynamin concentrate at discrete sites that are sparsely distributed across the plasma membrane remains poorly understood. Two dynamin-1 major splice variants differ by the length of their C-terminal proline-rich region (short-tail and long-tail). Using sptPALM in PC12 cells, neurons and MEF cells, we demonstrate that short-tail dynamin-1 isoforms ab and bb display an activity-dependent recruitment to the membrane, promptly followed by their concentration into nanoclusters. These nanoclusters are sensitive to both Calcineurin and dynamin GTPase inhibitors, and are larger, denser, and more numerous than that of long-tail isoform aa. Spatiotemporal modelling confirms that dynamin-1 isoforms perform distinct search patterns and undergo dimensional reduction to generate endocytic nanoclusters, with short-tail isoforms more robustly exploiting lateral trapping in the generation of nanoclusters compared to the long-tail isoform.
Topics: Animals; Dynamin I; Protein Isoforms; Endocytosis; PC12 Cells; Rats; Neurons; Mice; Cell Membrane; Calcineurin
PubMed: 38744819
DOI: 10.1038/s41467-024-47677-8 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... May 2024We investigated the utility of specific biomarkers-namely, c-terminal telopeptide (CTX), n-telopeptide (NTX), deoxypyridinoline (DPD), and tartrate-resistant acid...
BACKGROUND
We investigated the utility of specific biomarkers-namely, c-terminal telopeptide (CTX), n-telopeptide (NTX), deoxypyridinoline (DPD), and tartrate-resistant acid phosphatase (TRAP)-compared to conventional diagnostic methods. We hy-pothesized that these novel biomarkers could hold substantial value in the diagnosis, treatment, and monitoring of osteoporosis.
METHODS
The study was conducted over a three-year period, from January 1, 2020, to January 1, 2023. We enrolled a total of 520 patients aged 50 years or older who had been diagnosed with osteoporosis. Patients undergoing steroid treatments, which are known to contribute to osteoporosis, were excluded from the study. Additionally, we carefully selected and matched a control group consisting of 500 patients based on demographic characteristics relevant to the diagnosis of osteoporosis. This meticulous selection process resulted in a comprehensive cohort comprising 1,020 patients. Throughout the study, patients were closely monitored for a duration of one year to track the occurrence of pathological fractures and assess their overall prognosis.
RESULTS
As a result of our rigorous investigation, we identified CTX, NTX, DPD, and TRAP as pivotal biomarkers that play a crucial role in evaluating bone health, monitoring treatment effectiveness, and detecting pathological fractures in the context of osteoporosis.
CONCLUSION
Our study underscores the significance of these biomarkers in advancing the diagnosis and management of osteo-porosis, offering valuable insights into the disease's progression and treatment outcomes.
Topics: Humans; Biomarkers; Female; Osteoporosis; Male; Middle Aged; Aged; Collagen Type I; Bone Remodeling; Peptides; Tartrate-Resistant Acid Phosphatase; Amino Acids; Osteoporotic Fractures; Fractures, Spontaneous
PubMed: 38738676
DOI: 10.14744/tjtes.2024.48409 -
International Journal of Molecular... Apr 2024Overexpression of the 14-3-3ε protein is associated with suppression of apoptosis in cutaneous squamous cell carcinoma (cSCC). This antiapoptotic activity of 14-3-3ε...
Overexpression of the 14-3-3ε protein is associated with suppression of apoptosis in cutaneous squamous cell carcinoma (cSCC). This antiapoptotic activity of 14-3-3ε is dependent on its binding to CDC25A; thus, inhibiting 14-3-3ε - CDC25A interaction is an attractive therapeutic approach to promote apoptosis in cSCC. In this regard, designing peptide inhibitors of 14-3-3ε - CDC25A interactions is of great interest. This work reports the rational design of peptide analogs of pS, a CDC25A-derived peptide that has been shown to inhibit 14-3-3ε-CDC25A interaction and promote apoptosis in cSCC with micromolar IC. We designed new peptide analogs in silico by shortening the parent pS peptide from 14 to 9 amino acid residues; then, based on binding motifs of 14-3-3 proteins, we introduced modifications in the pS(174-182) peptide. We studied the binding of the peptides using conventional molecular dynamics (MD) and steered MD simulations, as well as biophysical methods. Our results showed that shortening the pS peptide from 14 to 9 amino acids reduced the affinity of the peptide. However, substituting Gln with either Phe or Tyr amino acids rescued the binding of the peptide. The optimized peptides obtained in this work can be candidates for inhibition of 14-3-3ε - CDC25A interactions in cSCC.
Topics: cdc25 Phosphatases; 14-3-3 Proteins; Protein Binding; Molecular Dynamics Simulation; Humans; Peptides; Amino Acid Sequence
PubMed: 38732131
DOI: 10.3390/ijms25094918 -
Molecular Biology Reports May 2024MicroRNAs are differentially expressed in periodontitis tissues. They are involved in cellular responses to inflammation and can be used as markers for diagnosing...
BACKGROUND
MicroRNAs are differentially expressed in periodontitis tissues. They are involved in cellular responses to inflammation and can be used as markers for diagnosing periodontitis. Microarray analysis showed that the expression level of microRNA-671-5p in periodontal tissues of patients with periodontitis was increased. In this study, we investigated the mechanism of action of microRNA-671-5p in human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions.
METHODS AND RESULTS
HPDLSCs were treated with lipopolysaccharide (LPS) to establish an inflammation model. The cell survival rate was determined using the cell counting kit-8 (CCK8). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses were used to detect the expression of microRNA-671-5p and dual-specificity phosphatase (DUSP) 8 proteins, respectively, Interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were detected using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter system was employed to determine the relationship between micoRNA-671-5p and DUSP8 expression. Activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway was confirmed using western blot analysis. Following the treatment of hPDLSCs with LPS, the expression levels of microRNA-671-5p in hPDLSCs were increased, cell viability decreased, and the expression of inflammatory factors displayed an increasing trend. MicroRNA-671-5p targets and binds to DUSP8. Silencing microRNA-671-5p or overexpressing DUSP8 can improve cell survival rate and reduce inflammatory responses. When DUSP8 was overexpressed, the expression of p-p38 was reduced.
CONCLUSIONS
microRNA-671-5p targets DUSP8/p38 MAPK pathway to regulate LPS-induced proliferation and inflammation in hPDLSCs.
Topics: Humans; Cell Survival; Cells, Cultured; Dual-Specificity Phosphatases; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; MicroRNAs; p38 Mitogen-Activated Protein Kinases; Periodontal Ligament; Periodontitis; Signal Transduction; Stem Cells
PubMed: 38727958
DOI: 10.1007/s11033-024-09510-9 -
Journal of the American Heart... May 2024S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous...
BACKGROUND
S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy.
METHODS AND RESULTS
Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice.
CONCLUSIONS
In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.
Topics: Animals; Calgranulin A; Fibroblast Growth Factors; Calgranulin B; Up-Regulation; NFATC Transcription Factors; Fibroblast Growth Factor-23; Disease Models, Animal; Myocytes, Cardiac; Signal Transduction; Cardiomegaly; Mice, Inbred C57BL; Male; Mice, Knockout; Calcineurin; Mice; Hypertrophy, Left Ventricular; Ventricular Remodeling
PubMed: 38726894
DOI: 10.1161/JAHA.122.028006 -
Journal of Nanobiotechnology May 2024Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic...
Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.
Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.
Topics: Animals; Humans; Male; Mice; Dual-Specificity Phosphatases; Epithelial Cells; Exosomes; Inflammation; MAP Kinase Signaling System; MicroRNAs; Pelvic Pain; Prostate; Prostatitis; Stromal Cells; Chemokine CCL2
PubMed: 38724995
DOI: 10.1186/s12951-024-02513-5 -
Autoimmunity Apr 2024Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of...
Increasing expression of dual-specificity phosphatase 12 mitigates oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway.
Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. However, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. This study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. In addition, DUSP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. In summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. These findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury.
Topics: Animals; Mice; Apoptosis; Cells, Cultured; Dual-Specificity Phosphatases; Glucose; Inflammation; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Neurons; Oxygen; p38 Mitogen-Activated Protein Kinases; Reperfusion Injury; Signal Transduction; Mitogen-Activated Protein Kinase 14
PubMed: 38721693
DOI: 10.1080/08916934.2024.2345919 -
European Journal of Medical Research May 2024Cell cycle protein-dependent kinase inhibitor protein 3 (CDKN3), as a member of the protein kinase family, has been demonstrated to exhibit oncogenic properties in...
BACKGROUND
Cell cycle protein-dependent kinase inhibitor protein 3 (CDKN3), as a member of the protein kinase family, has been demonstrated to exhibit oncogenic properties in several tumors. However, there are no pan-carcinogenic analyses for CDKN3.
METHODS
Using bioinformatics tools such as The Cancer Genome Atlas (TCGA) and the UCSC Xena database, a comprehensive pan-cancer analysis of CDKN3 was conducted. The inverstigation encompassed the examination of CDKN3 function actoss 33 different kinds of tumors, as well as the exploration of gene expressions, survival prognosis status, clinical significance, DNA methylation, immune infiltration, and associated signal pathways.
RESULTS
CDKN3 was significantly upregulated in most of tumors and correlated with overall survival (OS) of patients. Methylation levels of CDKN3 differed significantly between tumors and normal tissues. In addition, infiltration of CD4 + T cells, cancer-associated fibroblasts, macrophages, and endothelial cells were associated with CDKN3 expression in various tumors. Mechanistically, CDKN3 was associated with P53, PI3K-AKT, cell cycle checkpoints, mitotic spindle checkpoint, and chromosome maintenance.
CONCLUSION
Our pan-cancer analysis conducted in the study provides a comprehensive understanding of the involvement of CDKN3 gene in tumorigenesis. The findings suggest that targeting CDKN3 may potentially lead to novel therapeutic strategies for the treatment of tumors.
Topics: Humans; Neoplasms; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor Proteins; Prognosis; Gene Expression Regulation, Neoplastic; DNA Methylation; Computational Biology; Dual-Specificity Phosphatases
PubMed: 38720365
DOI: 10.1186/s40001-024-01869-6 -
Experimental Brain Research Jun 2024Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are...
Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer's disease and related tauopathies.
Topics: Animals; Alzheimer Disease; Mice, Transgenic; Tacrolimus; Calcineurin Inhibitors; Mice; Disease Models, Animal; Maze Learning; Calcineurin; Neuronal Plasticity; tau Proteins; Receptors, N-Methyl-D-Aspartate; Male; Synapses; Disks Large Homolog 4 Protein
PubMed: 38719948
DOI: 10.1007/s00221-024-06841-8