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European Review For Medical and... Apr 2024Methotrexate (MTX), a widely used chemotherapeutic and immunosuppressive agent, is associated with hepatotoxicity, leading to liver fibrosis and cirrhosis. This study...
OBJECTIVE
Methotrexate (MTX), a widely used chemotherapeutic and immunosuppressive agent, is associated with hepatotoxicity, leading to liver fibrosis and cirrhosis. This study explores the regenerative and reparative effects of fisetin, a flavonoid with known antioxidant and anti-inflammatory properties, on MTX-induced liver fibrosis in a rat model.
MATERIALS AND METHODS
Thirty-six male Wistar albino rats were divided into normal, MTX and saline, and MTX and fisetin. Liver injury was induced in the latter two groups using a single intraperitoneal dose of MTX (20 mg/kg). Fisetin (50 mg/kg/day) or saline was administered intraperitoneally for ten days. After sacrifice, liver tissues were subjected to histopathological evaluation and biochemical analyses, including Transforming Growth Factor-β1 (TGF-beta), sirtuins-1 (SIRT-1), malondialdehyde (MDA), cytokeratin 18, thrombospondin 1, and alanine transaminase (ALT) levels.
RESULTS
MTX administration significantly increased liver injury markers, including TGF-beta, MDA, cytokeratin 18, thrombospondin 1, and ALT, while reducing SIRT-1 levels. Fisetin treatment attenuated these effects, demonstrating its potential therapeutic impact. Histopathological analysis confirmed that fisetin mitigated MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration.
CONCLUSIONS
This study proves that fisetin administration can alleviate MTX-induced liver damage in rats. The reduction in oxidative stress, inflammation, and apoptosis, along with the histological improvements, suggests fisetin's potential as a therapeutic agent against MTX-induced hepatotoxicity. Further investigations and clinical studies are warranted to validate these findings and assess fisetin's translational potential in human cases of MTX-induced liver damage.
Topics: Methotrexate; Animals; Rats, Wistar; Male; Rats; Liver Cirrhosis; Flavonols; Flavonoids; Liver; Antioxidants; Sirtuin 1
PubMed: 38708470
DOI: 10.26355/eurrev_202404_36027 -
IScience May 2024During aging, skin homeostasis is essential for maintaining appearance, as well as biological defense of the human body. In this study, we identified thrombospondin-1...
During aging, skin homeostasis is essential for maintaining appearance, as well as biological defense of the human body. In this study, we identified thrombospondin-1 (THBS1) and fibromodulin (FMOD) as positive and negative regulators, respectively, of the TGF-β1-SMAD4 axis in human skin aging, based on and omics analyses and mathematical modeling. Using transcriptomic and epigenetic analyses of senescent dermal fibroblasts, TGF-β1 was identified as the key upstream regulator. Bifurcation analysis revealed a binary high-/low-TGF-β1 switch, with THBS1 as the main controller. Computational simulation of the TGF-β1 signaling pathway indicated that THBS1 expression was sensitively regulated, whereas FMOD was regulated robustly. Results of sensitivity analysis and validation showed that inhibition of SMAD4 complex formation was a promising method to control THBS1 production and senescence. Therefore, this study demonstrated the potential of combining data-driven target discovery with mathematical approaches to determine the mechanisms underlying skin aging.
PubMed: 38706856
DOI: 10.1016/j.isci.2024.109708 -
Molecular Therapy : the Journal of the... May 2024
Topics: Humans; Glioblastoma; Thrombospondin 1; Angiogenesis Inhibitors; Brain Neoplasms; Neovascularization, Pathologic; Animals
PubMed: 38702134
DOI: 10.1016/j.ymthe.2024.04.022 -
Frontiers in Bioscience (Landmark... Apr 2024The extracellular matrix (ECM) modeling induced by the metalloproteinases is a vital characteristic for tumor progression. Previous studies mainly focus on the functions...
Multi-Omics Pan-Cancer Analysis of Procollagen N-Propeptidase Gene Family of ADAMTS as Novel Biomarkers to Associate with Prognosis, Tumor Immune Microenvironment, Signaling Pathways, and Drug Sensitivities.
BACKGROUND
The extracellular matrix (ECM) modeling induced by the metalloproteinases is a vital characteristic for tumor progression. Previous studies mainly focus on the functions of two subgroups of metalloproteinases: matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) in tumors. The roles of another important group: the ADAMs with thrombospondin motifs (ADAMTS) remain unclear. This study aimed to perform a pan-cancer analysis of procollagen N-propeptidase subgroup of ADAMTS (PNPSA).
METHODS
We systematically analyzed expression landscape, genomic variations, prognostic value, and cell expression clusters of PNPSA in pan-cancer based on the multiple integrated open databases. Besides, we also analyzed the impacts of expressions and genomic variations of PNPSA members on tumor immune microenvironment (TIME) and immune-related molecules in pan-cancer based on the immune-related open databases. The Gene Set Variation Analysis (GSVA) was performed to evaluate the associations of the whole PNPSA with prognosis, tumor indicators, TIME, and drug sensitivities. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to reveal related signaling pathways. Finally, immunohistochemical staining was used to validate the differential analysis results.
RESULTS
We found a dual prognostic role of PNPSA members in pan-cancer and they were significantly correlated with TIME and immune-related molecules. Interestingly, the copy number variations (CNVs) of all PNPSA members were revealed to be negatively correlated with NK cell infiltration in most cancers. Single-cell sequencing analysis reveals expressions of PNPSA gene family members on some specific tumor and immune cells in addition to the fibroblasts. The GSVA score was found to have some predictive value for survival status in Brain Lower Grade Glioma (LGG), Mesothelioma (MESO), and Uveal Melanoma (UVM) and to be significantly correlated with tumorigenesis-related pathways such as PI3K-Akt, AGE-RAGE, etc. The GSVA score also shows some predictive value for chemotherapy and immunotherapy efficacy in some tumors.
CONCLUSIONS
PNPSA was correlated with tumor development and might be potential tumor biomarker and therapeutic target.
Topics: Humans; Tumor Microenvironment; Signal Transduction; Prognosis; Neoplasms; Biomarkers, Tumor; ADAMTS Proteins; Gene Expression Regulation, Neoplastic; Multiomics
PubMed: 38682182
DOI: 10.31083/j.fbl2904151 -
Cell Reports May 2024Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound...
Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 or the Atf4 gene antagonizes Thbs1-induced muscle atrophy. More importantly, Thbs1 mice show significantly reduced levels of denervation- and caloric restriction-mediated muscle atrophy, along with blunted TGFβ-Smad3-ATF4 signaling. Thus, Thbs1-mediated TGFβ-Smad3-ATF4 signaling in skeletal muscle regulates tissue rarefaction, suggesting a target for atrophy-based muscle diseases and sarcopenia with aging.
Topics: Animals; Male; Mice; Activating Transcription Factor 4; Autophagy; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Muscular Atrophy; Signal Transduction; Smad2 Protein; Smad3 Protein; Thrombospondin 1; Transforming Growth Factor beta
PubMed: 38678560
DOI: 10.1016/j.celrep.2024.114149 -
Thrombosis Research Jun 2024Use of anabolic-androgenic steroids (AAS) is associated with adverse cardiovascular (CV) effects, including potential prothrombotic effects. This study aimed to assess...
INTRODUCTION
Use of anabolic-androgenic steroids (AAS) is associated with adverse cardiovascular (CV) effects, including potential prothrombotic effects. This study aimed to assess platelet activation and aggregation, coagulation, and fibrinolysis, in long-term AAS users compared to non-using strength-trained athletes.
MATERIALS AND METHODS
Thirty-seven strength-trained men using AAS were compared to seventeen non-using professional strength-trained athletes at similar age (median 33 years). AAS use was verified by blood and urine analyses. Platelet Function Analyzer 100 (PFA-100) and whole blood impedance aggregometry with thrombin, arachidonic acid, and ADP as agonists, were performed to evaluate platelet aggregation. ELISA methods were used for markers of platelet activation. Fibrinogen, D-dimer, the coagulation inhibitors protein S and C activity, and antithrombin were measured by routine. Fibrinolysis was evaluated by Plasminogen Activator Inhibitor-1 (PAI-1) activity.
RESULTS
There were no significant differences in platelet aggregation between the two groups. Von Willebrand factor was lower among the AAS users (p < 0.01), and P-Selectin was slightly higher (p = 0.05), whereas CD40 Ligand, β-thromboglobulin, and thrombospondin did not differ significantly. No differences were found in the assessed coagulation inhibitors. Higher D-dimer levels (p < 0.01) and lower PAI-1 activity (p < 0.01) were found among the AAS users.
CONCLUSIONS
The investigated long-term users of AAS did not exhibit elevated platelet activity compared to strength-trained non-using athletes. However, AAS use was associated with higher D-dimer levels and lower PAI-1 activity. These findings suggest that any prothrombotic effect of long-term AAS use may predominantly involve other aspects of the hemostatic system than blood platelets.
Topics: Humans; Male; Fibrinolysis; Athletes; Blood Coagulation; Adult; Platelet Activation; Blood Platelets; Platelet Aggregation; Resistance Training; Anabolic Agents; Androgens
PubMed: 38676967
DOI: 10.1016/j.thromres.2024.04.027 -
Scientific Reports Apr 2024Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of...
Merozoite surface protein 3 of Plasmodium vivax (PvMSP3) contains a repertoire of protein members with unique sequence organization. While the biological functions of these proteins await elucidation, PvMSP3 has been suggested to be potential vaccine targets. To date, studies on natural immune responses to this protein family have been confined to two members, PvMSP3α and PvMSP3β. This study analyzed natural IgG antibody responses to PvMSP3γ recombinant proteins derived from two variants: one containing insert blocks (CT1230nF) and the other without insert domain (NR25nF). The former variant was also expressed as two subfragment proteins: one encompassing variable domain I and insert block A (CT1230N) and the other spanning from insert block B to conserved block III (CT1230C). Serum samples were obtained from 246 symptomatic vivax malaria patients in Tak (n = 50) and Ubon Ratchathani (n = 196) Provinces. In total, 176 (71.5%) patients could mount antibodies to at least one recombinant PvMSP3γ antigen. IgG antibodies directed against antigens CT1230nF, CT1230N, CT1230C and NR25nF occurred in 96.6%, 61.4%, 71.6% and 68.2% of samples, respectively, suggesting the widespread occurrence of B-cell epitopes across PvMSP3γ. The rates of seropositivity seemed to correlate with the number of previous malaria episodes. Isotype analysis of anti-PvMSP3γ antibodies has shown predominant cytophilic subclass responses, accounting for 75.4-81.7% for IgG1 and 63.6-77.5% for IgG3. Comparing with previous studies in the same cohort, the numbers of serum samples reactive to antigens derived from P. vivax merozoite surface protein 9 (PvMSP9) and thrombospondin-related anonymous protein (PvTRAP) were higher than those to PvMSP3γ, being 92.7% and 87.0% versus 71.5%, respectively. Three (1.22%) serum samples were nonresponsive to all these malarial proteins. Nevertheless, the relevance of naturally acquired antibodies to PvMSP3γ in host protection requires further studies.
Topics: Plasmodium vivax; Humans; Malaria, Vivax; Protozoan Proteins; Antigens, Protozoan; Antibodies, Protozoan; Immunoglobulin G; Male; Adult; Female; Middle Aged; Adolescent; Young Adult; Recombinant Proteins; Child
PubMed: 38671033
DOI: 10.1038/s41598-024-59153-w -
Frontiers in Psychiatry 2024Discovering biological markers is essential for understanding and treating mental disorders. Despite the limitations of current non-invasive methods, neural progenitor...
BACKGROUND
Discovering biological markers is essential for understanding and treating mental disorders. Despite the limitations of current non-invasive methods, neural progenitor cells from the olfactory epithelium (hNPCs-OE) have been emphasized as potential biomarker sources. This study measured soluble factors in these cells in Major Depressive Disorder (MDD), Borderline Personality Disorder (BPD), and healthy controls (HC).
METHODS
We assessed thirty-five participants divided into MDD (n=14), BPD (n=14), and HC (n=7). MDD was assessed using the Hamilton Depression Rating Scale. BPD was evaluated using the DSM-5 criteria and the Structured Clinical Interview for Personality Disorders. We isolated hNPCs-OE, collected intracellular proteins and conditioned medium, and quantified markers and soluble factors, including Interleukin-6, interleukin-8, and others. Analysis was conducted using one-way ANOVA or Kruskal-Wallis test and linear regression.
RESULTS
We found that hNPCs-OE of MDD and BPD decreased Sox2 and laminin receptor-67 kDa levels. MASH-1 decreased in BPD, while tubulin beta-III decreased in MDD compared to controls and BPD. Also, we found significant differences in IL-6, IL-8, MCP-1, and thrombospondin-1 levels between controls and MDD, or BPD, but not between MDD and BPD.
CONCLUSIONS
Altered protein markers are evident in the nhNPCs-OE in MDD and BPD patients. These cells also secrete higher concentrations of inflammatory cytokines than HC cells. The results suggest the potential utility of hNPCs-OE as an model for researching biological protein markers in psychiatric disorders. However, more extensive validation studies are needed to confirm their effectiveness and specificity in neuropsychiatric disorders.
PubMed: 38654728
DOI: 10.3389/fpsyt.2024.1283406 -
Oncology Letters Jun 2024Cluster of differentiation 47 (CD47) is a transmembrane protein that is widely and moderately expressed on the surface of various cells and can have an essential role in... (Review)
Review
Cluster of differentiation 47 (CD47) is a transmembrane protein that is widely and moderately expressed on the surface of various cells and can have an essential role in mediating cell proliferation, migration, phagocytosis, apoptosis, immune homeostasis and other related responses by binding to its ligands, integrins, thrombospondin-1 and signal regulatory protein α. The poor prognosis of cancer patients is closely associated with high expression of CD47 in glioblastoma, ovarian cancer, breast cancer, bladder cancer, colon cancer and hepatocellular carcinoma. Upregulation of CD47 expression facilitates the growth of numerous types of tumor cells, while downregulation of its expression promotes phagocytosis of tumor cells by macrophages, thereby limiting tumor growth. In addition, blocking CD47 activates the cyclic GMP-AMP (cGAMP) synthase/cGAMP/interferon gene stimulating factor signaling pathway and initiates an adaptive immune response that kills tumor cells. The present review describes the structure, function and interactions of CD47 with its ligands, as well as its regulation of phagocytosis and tumor cell fate. It summarizes the therapeutics, mechanisms of action, research advances and challenges of targeting CD47. In addition, this paper provides an overview of the latest therapeutic options for targeting CD47, such as chimeric antigen receptor (CAR) T-cells, CAR macrophages and nanotechnology-based delivery systems, which are essential for future clinical research on targeting CD47.
PubMed: 38646501
DOI: 10.3892/ol.2024.14389 -
Scientific Reports Apr 2024ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their...
ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system.
Topics: Fibrinolysin; von Willebrand Factor; ADAMTS13 Protein; ADAM Proteins; Tranexamic Acid; Ligands; Plasminogen
PubMed: 38643218
DOI: 10.1038/s41598-024-59672-6