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PloS One 2024Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and...
Osteoarthritis is the most prevalent type of degenerative arthritis. It is characterized by persistent pain, joint dysfunction, and physical disability. Pain relief and inflammation control are prioritised during osteoarthritis treatment Mume Fructus (Omae), a fumigated product of the Prunus mume fruit, is used as a traditional medicine in several Asian countries. However, its therapeutic mechanism of action and effects on osteoarthritis and articular chondrocytes remain unknown. In this study, we analyzed the anti-osteoarthritis and articular regenerative effects of Mume Fructus extract on rat chondrocytes. Mume Fructus treatment reduced the interleukin-1β-induced expression of matrix metalloproteinase 3, matrix metalloproteinase 13, and a disintegrin and metalloproteinase with thrombospondin type 1 motifs 5. Additionally, it enhanced collagen type II alpha 1 chain and aggrecan accumulation in rat chondrocytes. Furthermore, Mume Fructus treatment regulated the inflammatory cytokine levels, mitogen-activated protein kinase phosphorylation, and nuclear factor-kappa B activation. Overall, our results demonstrated that Mume Fructus inhibits osteoarthritis progression by inhibiting the nuclear factor-kappa B and mitogen-activated protein kinase pathways to reduce the levels of inflammatory cytokines and prevent cartilage degeneration. Therefore, Mume Fructus may be a potential therapeutic option for osteoarthritis.
Topics: Animals; Male; Rats; ADAMTS5 Protein; Aggrecans; Cartilage, Articular; Cells, Cultured; Chondrocytes; Collagen Type II; Down-Regulation; Fruit; Interleukin-1beta; MAP Kinase Signaling System; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Osteoarthritis; Plant Extracts; Prunus; Rats, Sprague-Dawley
PubMed: 38718039
DOI: 10.1371/journal.pone.0302906 -
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 -
Arab Journal of Gastroenterology : the... May 2024Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric...
BACKGROUND AND STUDY AIMS
Immunotherapy has emerged as a hot topic in cancer treatment in recent years and has also shown potential in the treatment of Helicobacter pylori-associated gastric cancer. However, there is still a need to identify potential immunotherapy targets.
MATERIAL AND METHODS
We used the GSE116312 dataset of Helicobacter pylori-associated gastric cancer to identify differentially expressed genes, which were then overlapped with immune genes from the ImmPort database. The identified immune genes were used to classify gastric cancer samples and evaluate the relationship between classification and tumor mutations, as well as immune infiltration. An immune gene-based prognostic model was constructed, and the expression levels of the genes involved in constructing the model were explored in the tumor immune microenvironment.
RESULTS
We successfully identified 60 immune genes and classified gastric cancer samples into two subtypes, which showed differences in prognosis, tumor mutations, immune checkpoint expression, and immune cell infiltration. Subsequently, we constructed an immune prognostic model consisting of THBS1 and PDGFD, which showed significant associations with macrophages and fibroblasts.
CONCLUSION
We identified abnormal expression of THBS1 and PDGFD in cancer-associated fibroblasts (CAFs) within the tumor immune microenvironment, suggesting their potential as therapeutic targets.
Topics: Stomach Neoplasms; Humans; Tumor Microenvironment; Helicobacter pylori; Helicobacter Infections; Thrombospondin 1; Prognosis; Platelet-Derived Growth Factor; Cancer-Associated Fibroblasts; Mutation; Lymphokines
PubMed: 38705811
DOI: 10.1016/j.ajg.2024.02.001 -
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 -
International Journal of Biological... May 2024Natto contains a potent fibrinolytic enzyme called nattokinase (NK), which has thrombolytic, antihypertensive, antiatherosclerotic and lipid-lowering effects. Although...
Natto contains a potent fibrinolytic enzyme called nattokinase (NK), which has thrombolytic, antihypertensive, antiatherosclerotic and lipid-lowering effects. Although NK has been recognized for its beneficial effect on humans with atherosclerotic cardiovascular disease (ASCVD), the underlying mechanisms involved in vascular inflammation-atherosclerosis development remain largely unknown. The current study aimed to explore the effects of NK on gene regulation, autophagy, necroptosis and inflammasome in vascular inflammation. The transcriptional profiles of NK in endothelial cells (ECs) by RNA sequencing (RNA-seq) revealed that NK affected THBS1, SRF and SREBF1 mRNA expression. In Q-PCR analysis, SRF and THBS1 were upregulated but SREBF1 was unaffected in ECs treated with NK. NK treatment induced autophagy and inhibited NLRP3 inflammasome and necroptosis in ECs. Furthermore, the inhibition of SRF or THBS1 by siRNA suppressed autophagy and enhanced the NLRP3 inflammasome and necroptosis. In a mouse model, NK reduced vascular inflammation by activating autophagy and inhibiting NLRP3 inflammasome and necroptosis. Our findings provide the first evidence that NK upregulates SRF and THBS1 genes, subsequently increasing autophagy and decreasing necroptosis and NLRP3 inflammasome formation to reduce vascular inflammation. Therefore, NK could serve as nutraceuticals or adjuvant therapies to reduce vascular inflammation and possible atherosclerosis progression.
Topics: Animals; Male; Mice; Autophagy; Endothelial Cells; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Subtilisins; Thrombospondin 1; Mice, Inbred C57BL
PubMed: 38679250
DOI: 10.1016/j.ijbiomac.2024.131779 -
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 -
International Journal of Biological... Jun 2024Endothelial repair is essential for restoring tissue fluid homeostasis following lung injury. R-spondin3 (RSPO3), a secreted protein mainly produced by endothelial cells...
Endothelial repair is essential for restoring tissue fluid homeostasis following lung injury. R-spondin3 (RSPO3), a secreted protein mainly produced by endothelial cells (ECs), has shown its protective effect on endothelium. However, the specific mechanisms remain unknown. To explore whether and how RSPO3 regulates endothelial regeneration after inflammatory vascular injury, the role of RSPO3 in sepsis-induced pulmonary endothelial injury was investigated in EC-specific RSPO3 knockdown, inducible EC-specific RSPO3 deletion mice, EC-specific RSPO3 overexpression mice, systemic RSPO3-administration mice, in isolated mouse lung vascular endothelial cells (MLVECs), and in plasma from septic patients. Here we show that plasma RSPO3 levels are decreased in septic patients and correlated with endothelial injury markers and PaO/FiO index. Both pulmonary EC-specific knockdown of RSPO3 and inducible EC-specific RSPO3 deletion inhibit pulmonary ECs proliferation and exacerbate ECs injury, whereas intra-pulmonary EC-specific RSPO3 overexpression promotes endothelial recovery and attenuates ECs injury during endotoxemia. We show that RSPO3 mediates pulmonary endothelial regeneration by a LGR4-dependent manner. Except for β-catenin, integrin-linked kinase (ILK)/Akt is also identified as a novel downstream effector of RSPO3/LGR4 signaling. These results conclude that EC-derived RSPO3 mediates pulmonary endothelial regeneration by LGR4-dependent activation of β-catenin and ILK signaling pathways after inflammatory vascular injury.
Topics: Animals; Thrombospondins; Protein Serine-Threonine Kinases; Mice; Signal Transduction; Humans; Regeneration; Receptors, G-Protein-Coupled; beta Catenin; Endothelial Cells; Lung; Vascular System Injuries; Cell Proliferation; Male; Sepsis; Inflammation
PubMed: 38677673
DOI: 10.1016/j.ijbiomac.2024.131805 -
Talanta Aug 2024An ultrasensitive immunosensor of Cys/Au@TiO based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was...
An ultrasensitive immunosensor of Cys/Au@TiO based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO. Firstly, HAuCl underwent a reduction reaction with NaBH, then Au nanoparticles were coated onto TiO nanoparticles. Followed, Cys/Au@TiO was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL (R = 0.991) and the limit of detection down to 0.77 pg ml, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.
Topics: Titanium; Gold; Humans; Liver Neoplasms; Biomarkers, Tumor; Prothrombin; Immunoassay; Biosensing Techniques; Cysteine; Metal Nanoparticles; Limit of Detection; Electrodes; Carcinoma, Hepatocellular; Protein Precursors; Biomarkers
PubMed: 38677167
DOI: 10.1016/j.talanta.2024.126082