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Discovery Medicine Dec 2023Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to...
BACKGROUND
Ischemic stroke is an acute cerebrovascular disease with high mortality rates and poor prognoses. The influence of ischemic stroke includes a heavy economic burden to patients and society, making the exploration of new therapeutic targets for preventing and treating ischemic stroke urgent. This study aimed to explore the effect of phosphoglycerate mutase family member 5 () on oxidative stress and mitochondrial dysfunction in ischemic stroke.
METHODS
The model of ischemic neuronal brain injury was established through culturing purchased human neuroblastoma cells (SH-SY5Y) by oxygen-glucose deprivation/reoxygenation (OGD/R). There were six experimental groups, including the OGD/R model group (SH-cells of OGD/R model), OE-NC group (cells of OGD/R model transfected with scramble cDNA), OE- group (cells of OGD/R model transfected with full-length sequence of ), si-NC group (cells of OGD/R model transfected with negative control small interference (si)RNA), si- group (cells of OGD/R model transfected with siRNA for knockdown), and a control group (cells cultured normally). Cell counting kit-8 (CCK-8) and flow cytometry were used to determine the activity and apoptosis of cells. Subsequently, the effects of expression on oxidative stress and mitochondrial dysfunction were analyzed. Mitochondrial morphology was observed by transmission electron microscopy (TEM), and mitochondrial membrane potential (MMP) was determined by JC-1 fluorescent probe. The levels of reactive oxygen species (ROS) were measured by flow cytometry, and levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA) assay. The expression of light chain (LC)3-II/I and autophagy-related gene 5 (ATG5) proteins were measured, and the regulation of expression on -induced putative protein kinase 1 ()/ pathway was also explored.
RESULTS
overexpression in OGD/R cells decreased the cell viability ( < 0.001) while increasing cell apoptosis ( < 0.01) compared to the OGD/R group. Inhibition of expression reversed the decreased cell viability ( < 0.001) and the increased cell apoptosis ( < 0.01). The JC-1 fluorescence showed that OGD/R treatment reduced mitochondrial membrane potential ( < 0.001) and TEM showed an obvious increase in phagosomes. In addition, OGD/R treatment enhanced oxidative stress (increased ROS, < 0.01; increased MDA, < 0.001; decreased SOD, < 0.001), which could be further enhanced by overexpression of (ROS, < 0.001; MDA, < 0.001; SOD, < 0.001) while reversed by the inhibition of (ROS, < 0.01; MDA, < 0.001; SOD, < 0.001). The OGD/R-activated / pathway was inhibited by the knockdown of ( < 0.01) but promoted by the overexpression of ( < 0.05).
CONCLUSIONS
stimulates oxidative stress and impairs mitochondrial function in ischemic stroke, and regulates the / signaling pathway. Therefore, is likely to be a target for the therapy of ischemic stroke.
Topics: Humans; Reactive Oxygen Species; Ischemic Stroke; Neuroblastoma; Oxygen; Protein Kinases; Ubiquitin-Protein Ligases; Superoxide Dismutase; Mitochondrial Diseases; Glucose; Apoptosis; Phosphoprotein Phosphatases; Mitochondrial Proteins
PubMed: 38058078
DOI: 10.24976/Discov.Med.202335179.109 -
Biomedicine & Pharmacotherapy =... Sep 2023The nuclear factor of activated T cells (NFAT) was first identified as a transcriptional regulator of activated T cells. The NFAT family is involved in the development... (Review)
Review
The nuclear factor of activated T cells (NFAT) was first identified as a transcriptional regulator of activated T cells. The NFAT family is involved in the development of tumors. Furthermore, recent evidence reveals that NFAT proteins regulate the development of inflammatory and immune responses. New discoveries have also been made about the mechanisms by which NFAT regulates cancer progression through cancer stem cells (CSC). Here, we discuss the role of the NFAT family in the immune system and various cancer types.
Topics: Humans; NFATC Transcription Factors; Calcineurin; Neoplasms; Signal Transduction; Neoplastic Stem Cells
PubMed: 37454598
DOI: 10.1016/j.biopha.2023.115167 -
Journal of Ethnopharmacology Jan 2024Dohongsammul-tang (DH) is a Korean traditional herbal medicine used to alleviate symptoms caused by extravasated blood. It is known to protect against cardiovascular...
ETHNOPHARMACOLOGICAL RELEVANCE
Dohongsammul-tang (DH) is a Korean traditional herbal medicine used to alleviate symptoms caused by extravasated blood. It is known to protect against cardiovascular diseases and promote blood circulation by activating blood circulation to dispel blood stasis. The DH based on the characteristics of its medicinal properties has discovered the potential of alleviating cardiac hypertrophy. Therefore, this study was performed to verify the pharmacological effect of DH on improving cardiovascular disorders and to demonstrate its mutual improvement effect on renal function. Furthermore, aim of this study is founding the new potential beyond the traditional medicinal efficacy of DH, a traditional medicine.
AIM OF THE STUDY
In cardiovascular disease, cardiac hypertrophy refers to a change in the shape of the heart's structure due to pressure overload. It is known that an increase in myofibrils causes thickening of the heart, resulting in high blood pressure. Therefore, suppressing cardiac hypertrophy may be a major factor in lowering the morbidity, mortality, and heart failure associated with cardiovascular disease. Therefore, the study was performed to investigate whether DH, traditionally used, has effects on improving and alleviating cardiac injury and fibrosis caused by cardiac hypertrophy.
MATERIALS AND METHODS
Dohongsamul-tang was composed of 6 herbal medicine and each material were boiled with 4 L distilled water for 2 h. The mixture for dohongsamul-tang centrifuged at 3000 rpm for 10 min and concentrated. The concentrated dohongsamul-tang extraction freeze-dried and sotred at 70 °C. The powder of dohongsamul-tang was diluted with distilled water and administered orally. In this study, pressure overload was induced by tying the transverse aortic arch, which is connected to the left ventricle, to the thickness of a 27G needle by performing a surgical operation. The resulting cardiac hypertrophy and heart remodeling was induced and maintained for 8 weeks.
RESULTS
The study administered propranolol and dohongsamul-tang orally for 10 weeks to investigate their effects on cardiac hypertrophy induced by transverse aortic contraction (TAC) surgery. Results showed that TAC group increased the left ventricle weight and decreased cardiac function, but dohongsamul-tang treatment attenuated these effects. The pressure-volume curve experiment revealed that dohongsamul-tang improved cardiovascular function, which was worsened by TAC group. Dohongsamul-tang treatment also downregulated collagen I and III through the TGF-β/Smad2 signaling pathway and improved hematological biomarkers of cardiac hypertrophy. In addition, dohongsamul-tang treatment improved renal function-related biomarkers, such as blood creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin, which were increased by TAC-induced cardiac hypertrophy.
CONCLUSIONS
Taken together, dohongsamul-tang treatment inhibited cardiac remodeling due to pressure overload in the TAC-induced cardiac hypertrophy model, and this effect is thought to be manifested by improving the functional and morphological changes through the calcineurin/NFATc4 and reducing the cardiac fibrosis by suppressing TGF-β/Smad2 signaling pathways.
Topics: Animals; Mice; Calcineurin; Cardiovascular Diseases; Ventricular Remodeling; Cardiomegaly; Fibrosis; Transforming Growth Factor beta; Plant Extracts; Water; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37453625
DOI: 10.1016/j.jep.2023.116844 -
Brain, Behavior, and Immunity Mar 2024Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6...
BACKGROUND
Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD.
METHODS
Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies.
RESULTS
A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD.
CONCLUSIONS
Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.
Topics: Humans; Genome-Wide Association Study; Interleukin-6; Parkinson Disease; Prospective Studies; Inflammation; C-Reactive Protein; Genetic Risk Score; Protein Phosphatase 2C
PubMed: 38336023
DOI: 10.1016/j.bbi.2024.02.013 -
Haematologica Dec 2023Clonal hematopoiesis (CH) is an age-related condition driven by stem and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential...
Clonal hematopoiesis (CH) is an age-related condition driven by stem and progenitor cells harboring recurrent mutations linked to myeloid neoplasms. Currently, potential effects on hematopoiesis, stem cell function and regenerative potential under stress conditions are unknown. We performed targeted DNA sequencing of 457 hematopoietic stem cell grafts collected for autologous stem cell transplantation (ASCT) in myeloma patients and correlated our findings with high-dimensional longitudinal clinical and laboratory data (26,510 data points for blood cell counts/serum values in 25 days around transplantation). We detected CHrelated mutations in 152 patients (33.3%). Since many patients (n=54) harbored multiple CH mutations in one or more genes, we applied a non-negative matrix factorization (NMF) clustering algorithm to identify genes that are commonly co-mutated in an unbiased approach. Patients with CH were assigned to one of three clusters (C1-C3) and compared to patients without CH (C0) in a gene specific manner. To study the dynamics of blood cell regeneration following ASCT, we developed a time-dependent linear mixed effect model to validate differences in blood cell count trajectories amongst different clusters. The results demonstrated that C2, composed of patients with DNMT3A and PPM1D single and co-mutated CH, correlated with reduced stem cell yields and delayed platelet count recovery following ASCT. Also, the benefit of maintenance therapy was particularly strong in C2 patients. Taken together, these data indicate an impaired regenerative potential of hematopoietic stem cell grafts harboring CH with DNMT3A and PPM1D mutations.
Topics: Humans; Clonal Hematopoiesis; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Hematopoiesis; Mutation; Regeneration; Protein Phosphatase 2C
PubMed: 37381752
DOI: 10.3324/haematol.2023.282992 -
International Immunopharmacology Oct 2023Angiopoietin-like protein 2 (ANGPTL2) was implicated in various cardiovascular diseases; however, its role in lipopolysaccharide (LPS)-related septic cardiomyopathy...
Angiopoietin-like protein 2 (ANGPTL2) was implicated in various cardiovascular diseases; however, its role in lipopolysaccharide (LPS)-related septic cardiomyopathy remains unclear. Herein, mice were exposed to LPS to generate septic cardiomyopathy, and adeno-associated viral vector was employed to overexpress ANGPTL2 in the myocardium. Besides, mice were treated with adenoviral vector to knock down ANGPTL2 in hearts. ANGPTL2 expressions in hearts and cardiomyocytes were upregulated by LPS challenge. ANGPTL2 overexpression aggravated, while ANGPTL2 silence ameliorated LPS-associated cardiac impairment and inflammation. Mechanically, we found that ANGPTL2 activated NLRP3 inflammasome via suppressing DUSP1 signaling, and NLRP3 knockdown abrogated the detrimental role of ANGPTL2 in aggravating LPS-induced cardiac inflammation. Furthermore, DUSP1 overexpression significantly inhibited ANGPTL2-mediated NLRP3 activation, and subsequently improved LPS-related cardiac dysfunction. In summary, ANGPTL2 exacerbated septic cardiomyopathy via activating NLRP3-mediated inflammation in a DUSP1-dependent manner, and our study uncovered a promising therapeutic target in preventing septic cardiomyopathy.
Topics: Animals; Mice; Angiopoietin-Like Protein 2; Cardiomyopathies; Inflammasomes; Inflammation; Lipopolysaccharides; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Dual Specificity Phosphatase 1
PubMed: 37531825
DOI: 10.1016/j.intimp.2023.110701 -
International Journal of Molecular... Jul 2023Protein phosphatase 2A (PP2A) is a strongly conserved and major protein phosphatase in all eukaryotes. The canonical PP2A complex consists of a catalytic (C),... (Review)
Review
Protein phosphatase 2A (PP2A) is a strongly conserved and major protein phosphatase in all eukaryotes. The canonical PP2A complex consists of a catalytic (C), scaffolding (A), and regulatory (B) subunit. Plants have three groups of evolutionary distinct B subunits: B55, B' (B56), and B''. Here, the Arabidopsis B' group is reviewed and compared with other eukaryotes. Members of the B'α/B'β clade are especially important for chromatid cohesion, and dephosphorylation of transcription factors that mediate brassinosteroid (BR) signaling in the nucleus. Other B' subunits interact with proteins at the cell membrane to dampen BR signaling or harness immune responses. The transition from vegetative to reproductive phase is influenced differentially by distinct B' subunits; B'α and B'β being of little importance, whereas others (B'γ, B'ζ, B'η, B'θ, B'κ) promote transition to flowering. Interestingly, the latter B' subunits have three motifs in a conserved manner, i.e., two docking sites for protein phosphatase 1 (PP1), and a POLO consensus phosphorylation site between these motifs. This supports the view that a conserved PP1-PP2A dephosphorelay is important in a variety of signaling contexts throughout eukaryotes. A profound understanding of these regulators may help in designing future crops and understand environmental issues.
Topics: Arabidopsis; Arabidopsis Proteins; Phosphorylation; Physiological Phenomena; Protein Phosphatase 2; Protein Subunits; Transcription Factors
PubMed: 37569631
DOI: 10.3390/ijms241512255 -
Biochimica Et Biophysica Acta.... Feb 2024Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in...
OBJECTIVES
Secreted frizzled-related protein 2 (SFRP2), a novel adipokine that used to be considered an inhibitor of the canonical Wnt pathway, may play a protective role in metabolic disorders. However, its effect on diabetic cardiomyopathy was still unclear. Accumulating evidence indicates that mitophagy can protect cardiac function in the diabetic heart. The present study aimed to explore the roles of SFRP2 on diabetic cardiomyopathy, focusing on the effects and mechanisms for regulating mitophagy.
METHODS
Wild-type H9c2 cells, Sfrp2 overexpression and knockdown H9c2 cells were exposed to a glucolipotoxic milieu. Reactive oxygen species (ROS) production, cell viability, apoptosis, mitophagy and lysosomal activity were detected. The interaction of SFRP2 with frizzled 5 (FZD5), and its effect on expression and intracellular localization of transcription factor EB (TFEB) and β-catenin were also explored. Diabetic rats and Sfrp2 overexpression diabetic rats were constructed to further document the findings from the in vitro study.
RESULTS
The expression of SFRP2 was low and mitophagy was inhibited in H9c2 cells in a glucolipotoxic milieu. Sfrp2 overexpression activated mitophagy and reduced H9c2 cells injury, whereas Sfrp2 deficiency inhibited mitophagy and worsened this injury. Consistent with the in vitro findings, Sfrp2 overexpression ameliorated the impairment in cardiac function of diabetic rats by activating mitophagy. Sfrp2 overexpression upregulated the expression of calcineurin and TFEB, but did not affect β-catenin in vitro and in vivo. The calcineurin inhibitor tacrolimus can inhibit mitophagy and worsen cell injury in Sfrp2 overexpression H9c2 cells. Furthermore, we found that FZD5 is required for the SFRP2-induced activation of the calcineurin/TFEB pathway and interacts with SFRP2 in H9c2 cells. Transfection with small interfering RNA targeting FZD5 opposed the effects of Sfrp2 overexpression on mitophagy and cell survival in a glucolipotoxic environment.
CONCLUSIONS
SFRP2 can protect the diabetic heart by interacting with FZD5 and activating the calcineurin/TFEB pathway to upregulate mitophagy in H9c2 cells.
Topics: Rats; Animals; beta Catenin; Secreted Frizzled-Related Proteins; Mitophagy; Diabetic Cardiomyopathies; Diabetes Mellitus, Experimental; Calcineurin; Membrane Proteins
PubMed: 38101654
DOI: 10.1016/j.bbadis.2023.166989 -
JCI Insight Oct 2023Overexpression of phosphatases of regenerating liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient...
Overexpression of phosphatases of regenerating liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in patients with acute myeloid leukemia (AML). In the current study, a PTEN-knockdown AML animal model was generated to assess the effect of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the BM niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN and downregulation of AKT/mTOR-regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.
Topics: Animals; Humans; Signal Transduction; PTEN Phosphohydrolase; Leukemia, Myeloid, Acute; Hematopoietic Stem Cells
PubMed: 37665633
DOI: 10.1172/jci.insight.170065 -
Nature Communications Jan 2024DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive...
DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive upstream regulator of Lck during T-cell activation. DUSP22 dephosphorylates UBR2 at specific Serine residues, leading to ubiquitin-mediated UBR2 degradation. UBR2 is also modified by the SCF E3 ubiquitin ligase complex via Lys48-linked ubiquitination at multiple Lysine residues. Single-cell RNA sequencing analysis and UBR2 loss of function experiments showed that UBR2 is a positive regulator of proinflammatory cytokine expression. Mechanistically, UBR2 induces Lys63-linked ubiquitination of Lck at Lys99 and Lys276 residues, followed by Lck Tyr394 phosphorylation and activation as part of TCR signalling. Inflammatory phenotypes induced by TCR-triggered Lck activation or knocking out DUSP22, are attenuated by genomic deletion of UBR2. UBR2-Lck interaction and Lck Lys63-linked ubiquitination are induced in the peripheral blood T cells of human SLE patients, which demonstrate the relevance of the UBR2-mediated regulation of inflammation to human pathology. In summary, we show here an important regulatory mechanism of T cell activation, which finetunes the balance between T cell response and aggravated inflammation.
Topics: Humans; Ubiquitination; Ubiquitin-Protein Ligases; Phosphorylation; Dual-Specificity Phosphatases; Inflammation; Receptors, Antigen, T-Cell; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mitogen-Activated Protein Kinase Phosphatases
PubMed: 38225265
DOI: 10.1038/s41467-024-44843-w