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Journal of Zhejiang University.... Jun 2024Osteoarthritis (OA) is a chronic progressive osteoarthropathy in the elderly. Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in...
Osteoarthritis (OA) is a chronic progressive osteoarthropathy in the elderly. Osteoclast activation plays a crucial role in the occurrence of subchondral bone loss in early OA. However, the specific mechanism of osteoclast differentiation in OA remains unclear. In our study, gene expression profiles related to OA disease progression and osteoclast activation were screened from the Gene Expression Omnibus (GEO) repository. GEO2R and Funrich analysis tools were employed to find differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that chemical carcinogenesis, reactive oxygen species (ROS), and response to oxidative stress were mainly involved in osteoclast differentiation in OA subchondral bone. Furthermore, fourteen DEGs that are associated with oxidative stress were identified. The first ranked differential gene, heme oxygenase 1 (), was selected for further validation. Related results showed that osteoclast activation in the pathogenesis of OA subchondral bone is accompanied by the downregulation of . Carnosol was revealed to inhibit osteoclastogenesis by targeting and upregulating the expression of antioxidant protein in vitro. Meanwhile, carnosol was found to alleviate the severity of OA by inhibiting the activation of subchondral osteoclasts in vivo. Our research indicated that the activation of osteoclasts due to subchondral bone redox dysplasia may serve as a significant pathway for the advancement of OA. Targeting in subchondral osteoclasts may offer novel insights for the treatment of early OA.
Topics: Heme Oxygenase-1; Osteoarthritis; Osteoclasts; Humans; Animals; Oxidative Stress; Cell Differentiation; Osteogenesis; Male; Mice; Reactive Oxygen Species
PubMed: 38910496
DOI: 10.1631/jzus.B2300303 -
Cardio-oncology (London, England) Jun 2024Doxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options....
BACKGROUND
Doxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options. We previously reported that Red Ginseng (steamed and dried the root of Panax Ginseng cultivated for over six years; RGin) is beneficial for the treatment of DICM. However, the mechanism underlying the action of RGin remains unclear. In this study, we investigated the mechanism of action underlying the efficacy of RGin in the treatment of DICM.
METHODS
Four-week-old DBA/2 mice were divided into: vehicle, DXR, RGin, and DXR + RGin (n = 10/group). Mice were treated with DXR (4 mg/kg, once a week, accumulated 20 mg/kg, i.p.) or RGin (0.5 g/kg, three times a week, i.p.). To evaluate efficacy, the survival rate and left ventricular ejection fraction (LVEF) were measured as a measure of cardiac function, and cardiomyocytes were subjected to Masson trichrome staining. To investigate the mechanism of action, western blotting was performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, transferrin receptor (TfR), and other related proteins. Data were analyzed using the Easy R software. Between-group comparisons were performed using one-way analysis of variance and analyzed using a post-hoc Tukey test. Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. P < 0.05 was considered statistically significant in all analyses.
RESULTS
RGin treatment prolongs survival and protects against reduced LVEF. In the DXR group, Nrf2 was not activated and cell death was accelerated. Furthermore, there was an increase in the TfR levels, suggesting abnormal iron metabolism. However, the DXR + RGin group showed activation of the Nrf2 pathway and suppression of myocardial cell death. Furthermore, there was no increase in TfR expression, suggesting that there were no abnormalities in iron metabolism. Therefore, the mechanism of action of RGin in DICM involves an increase in antioxidant activity and inhibition of cell death through activation of the Nrf2 pathway.
CONCLUSION
RGin is a useful therapeutic candidate for DICM. Its efficacy is supported by the activation of the Nrf2 pathway, which enhances antioxidant activity and inhibits cell death.
PubMed: 38909271
DOI: 10.1186/s40959-024-00242-0 -
Lipids in Health and Disease Jun 2024Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they...
BACKGROUND
Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community.
METHOD
This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes.
RESULTS
7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate.
CONCLUSION
In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.
Topics: Animals; Diet, High-Fat; Adipogenesis; Obesity; Mice; 3T3-L1 Cells; Adipocytes; Mice, Inbred C57BL; Male; PPAR gamma; Sterol Regulatory Element Binding Protein 1; Stearoyl-CoA Desaturase; Mice, Obese; Fatty Acid-Binding Proteins; Adipokines; Anti-Obesity Agents; Uncoupling Protein 1; Adipose Tissue, White; CCAAT-Enhancer-Binding Proteins
PubMed: 38909257
DOI: 10.1186/s12944-024-02175-0 -
Scientific Reports Jun 2024Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds;...
Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds; 4-hydroxybenzaldehyde (1), 4-hydroxybenzoic acid (2), tyrosol (3), azelaic acid (4), malic acid (5), and fusaric acid (6). Fungal extract as well as its metabolites were evaluated for their anti-inflammatory and anti-hyperpigmentation potential via in vitro cyclooxygenases and tyrosinase inhibition assays, respectively. Azelaic acid (4) exhibited powerful and selective COX-2 inhibition followed by fusaric acid (6) with IC values (2.21 ± 0.06 and 4.81 ± 0.14 μM, respectively). As well, azelaic acid (4) had the most impressive tyrosinase inhibitory effect with IC value of 8.75 ± 0.18 μM compared to kojic acid (IC = 9.27 ± 0.19 μM). Exclusive computational studies of azelaic acid and fusaric acid with COX-2 were in good accord with the in vitro results. Interestingly, this is the first time to investigate and report the potential of compounds 3-6 to inhibit cyclooxygenase enzymes. One of the most invasive forms of skin cancer is melanoma, a molecular docking study using a set of enzymes related to melanoma suggested pirin to be therapeutic target for azelaic acid and fusaric acid as a plausible mechanism for their anti-melanoma activity.
Topics: Fusarium; Anti-Inflammatory Agents; Dicarboxylic Acids; Molecular Docking Simulation; Melanoma; Humans; Cyclooxygenase 2; Fusaric Acid; Monophenol Monooxygenase; Computer Simulation; Cyclooxygenase Inhibitors
PubMed: 38909081
DOI: 10.1038/s41598-024-63958-0 -
European Journal of Pharmacology Jun 2024Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted...
Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspase-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increased indicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs); cIAP1, XIAP and survivin were decreased, creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug.
PubMed: 38908670
DOI: 10.1016/j.ejphar.2024.176764 -
Medicine Jun 2024Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA)...
Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA) desaturation. Stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturase 2 (FADS2) are two key rate-limiting enzymes that catalyze the FA desaturation process and cooperate to accelerate lipid metabolic activities. In this study, we investigated the potential functions of SCD and FADS2 in BRCA using bioinformatic analysis and experimental validation. The gene expression profiling interactive analysis database showed that the expression of SCD or FADS2 genes was positively linked to worse overall survival and disease-free survival in the Cancer Genome Atlas database-BRCA. The University of Alabama at Birmingham cancer data analysis portal database indicates that the expression and methylation levels of SCD or FADS2 are associated with various clinicopathological factors in patients with BRCA. Moreover, the tumor immune estimation resource and TISCH databases showed a significant positive correlation between the expression of SCD and the abundance of CD8+ T cells and macrophage cell infiltration, while the expression of FADS2 was positively correlated with the abundance of B cells. Meanwhile, SCD or FADS2 had a higher expression in monocytes/macrophages analyzed the BRCA_GSE143423 and BRCA_GSE114727_inDrop datasets. Mechanistically, the Search Tool for the Retrieval of Distant Genes and CancerSEA databases showed that SCD and FADS2 were upregulated in several cell biology signaling pathways, particularly in inflammation, apoptosis, and DNA repair. Finally, SCD or FADS2 knockdown inhibited the proliferation of MCF-7 and MDA-MB-231 cells. In summary, SCD and FADS2 play significant roles in BRCA development, suggesting that they may serve as potential therapeutic targets for BRCA treatment.
Topics: Humans; Fatty Acid Desaturases; Breast Neoplasms; Female; Tumor Microenvironment; Prognosis; Stearoyl-CoA Desaturase; Mutation; Gene Expression Regulation, Neoplastic
PubMed: 38905386
DOI: 10.1097/MD.0000000000038597 -
Science Advances Jun 2024Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and...
Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.
Topics: Immunotherapy; Animals; Mice; Humans; Autophagy; Cell Line, Tumor; Proteolysis; Neoplasms; Nanoparticles; Methotrexate; Indoleamine-Pyrrole 2,3,-Dioxygenase; Dendritic Cells
PubMed: 38905336
DOI: 10.1126/sciadv.adn8079 -
Bioscience Reports Jun 2024
Expression of Concern: Madecassoside protects retinal pigment epithelial cells against hydrogen peroxide induced oxidative stress and apoptosis through the activation of Nrf2/HO-1 pathway.
Topics: NF-E2-Related Factor 2; Oxidative Stress; Hydrogen Peroxide; Apoptosis; Humans; Heme Oxygenase-1; Retinal Pigment Epithelium; Signal Transduction; Triterpenes; Epithelial Cells; Cell Line; Membrane Proteins; Animals
PubMed: 38904175
DOI: 10.1042/BSR-2019-4347_EOC -
Journal of Inflammation Research 2024Intervertebral disc degeneration (IDD) underlies the pathogenesis of degenerative diseases of the spine; however, its exact molecular mechanism is unclear.
BACKGROUND
Intervertebral disc degeneration (IDD) underlies the pathogenesis of degenerative diseases of the spine; however, its exact molecular mechanism is unclear.
PURPOSE
To explore the molecular mechanism of mechanical pressure (MP)-induced IDD and to assess the role and mechanism of Rosuvastatin (RSV) inhibits MP-induced IDD.
METHODS
SD rat nucleus pulposus cells (NPCs) were cultured in vitro and an apoptosis model of NPCs was constructed using MP. Proliferative activity, reactive oxygen species content, apoptosis, and wound healing were detected in each group of NPCs, respectively. The expression of relevant proteins was detected by qPCR and Western Blot techniques. 18 SD rats were randomly divided into control, pressure and RSV groups. Elisa, qPCR, Western Blot and immunohistochemical staining techniques were used to detect changes in the content of related proteins in the intervertebral discs of each group. HE staining and Modified Saffron-O and Fast Green Stain Kit were used to assess IDD in each group.
RESULTS
MP treatment at 1.0 MPa could significantly induce apoptosis of NPCs after 24 h. MP could significantly inhibit the proliferative activity and wound healing ability of NPCs, and increase the intracellular reactive oxygen species content and apoptosis rate; pretreatment with RSV could significantly activate the Nrf2/HO-1 signaling pathway and reverse the cellular damage caused by MP; when inhibit the Nrf2/HO-1 signaling pathway activation, the protective effect of RSV was reversed. In vivo MP could significantly increase the content of inflammatory factors within the IVD and promote the degradation of extracellular matrix, leading to IDD. When the intervention of RSV was employed, it could significantly activate the Nrf2/HO-1 signaling pathway and improve the above results.
CONCLUSION
RSV may inhibit MP-induced NPCs damage and IDD by activating the Nrf2/HO-1 signaling pathway.
PubMed: 38903877
DOI: 10.2147/JIR.S461348 -
Biomedicine & Pharmacotherapy =... Jun 2024Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and...
Phenylsulfate-induced oxidative stress and mitochondrial dysfunction in podocytes are ameliorated by Astragaloside IV activation of the SIRT1/PGC1α /Nrf1 signaling pathway.
Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and shields podocytes from oxidative stress (OS) and mitochondrial dysfunction remain poorly understood. In this study, we used biochemical assays, histopathological analysis, Doppler ultrasound, transmission electron microscopy,flow cytometry, fluorescence staining, and Western blotting and other methods. AS-IV was administered to db/db mice for in vivo experimentation. Our findings indicated that AS-IV treatment significantly reduced diabetes-associated markers, proteinuria, and kidney damage. It also diminished ROS levels in the kidney, enhanced the expression of endogenous antioxidant enzymes, and improved mitochondrial health. Phenyl sulfate (PS), a protein-bound uremic solute of enteric origin, has been closely linked with DN and represents a promising avenue for further research. In vitro, PS exposure induced OS and mitochondrial dysfunction in podocytes, increasing ROS levels while decreasing antioxidant enzyme activity (Catalase, Heme Oxygenase-1, Superoxide Dismutase, and Glutathione Peroxidase). ROS inhibitors (N-acetyl-L-cysteine, NAC) as the positive control group can significantly reduce the levels of ROS and restore antioxidant enzymes protein levels. Additionally, PS reduced markers associated with mitochondrial biosynthesis and function (SIRT1, PGC1α, Nrf1, and TFAM). These adverse effects were partially reversed by AS-IV treatment. However, co-treatment with AS-IV and the SIRT1 inhibitor EX527 failed to restore these indicators. Overall, our study demonstrates that AS-IV effectively attenuates DN and mitigates PS-induced OS and mitochondrial dysfunction in podocytes via the SIRT1/PGC1α/Nrf1 pathway.
PubMed: 38901196
DOI: 10.1016/j.biopha.2024.117008