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International Immunopharmacology Jun 2024Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to...
BACKGROUND
Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action.
METHOD
An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action.
RESULTS
Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45CD11bGr-1 cell upregulation, which significantly inhibited the proliferation of CD4 T lymphocytes in vitro and exhibited a CD31 phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD.
CONCLUSION
This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.
PubMed: 38851157
DOI: 10.1016/j.intimp.2024.112429 -
Biomedicines Apr 2024Obesity results in hepatic fat accumulation, i.e., steatosis. In addition to fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid...
Hepatocyte-Specific PEX16 Abrogation in Mice Leads to Hepatocyte Proliferation, Alteration of Hepatic Lipid Metabolism, and Resistance to High-Fat Diet (HFD)-Induced Hepatic Steatosis and Obesity.
Obesity results in hepatic fat accumulation, i.e., steatosis. In addition to fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in the mitochondria and peroxisomes. Usually, very long-chain and branched-chain fatty acids are the first to be oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in the mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout () mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high-fat diet (HFD) feeding, body weights were increased in PEX16 floxed () mice and adipose-specific PEX16 knockout () mice, but not in the mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. HFD increased liver mass in the mice but somehow reduced the already enlarged liver mass in the mice. The basal levels of serum triglyceride, free fatty acids, and cholesterol were decreased, whereas serum bile acids were increased in the mice, and HFD-induced steatosis was not observed in the mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.
PubMed: 38790950
DOI: 10.3390/biomedicines12050988 -
Biomedicines Apr 2024Gliomas are the most common primary brain tumors in adults. Despite multidisciplinary treatment approaches, the survival rates for patients with malignant glioma have...
Gliomas are the most common primary brain tumors in adults. Despite multidisciplinary treatment approaches, the survival rates for patients with malignant glioma have only improved marginally, and few prognostic biomarkers have been identified. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a crucial regulator of cancer metabolism, playing a vital role in cancer cell adaptation to fluctuating energy demands. In this study, the clinicopathological roles of PGC-1α in gliomas were evaluated. Employing immunohistochemistry, cell culture, siRNA transfection, cell viability assays, western blot analyses, and in vitro and in vivo invasion and migration assays, we explored the functions of PGC-1α in glioma progression. High PGC-1α expression was significantly associated with an advanced pathological stage in patients with glioma and with poorer overall survival. The downregulation of PGC-1α inhibited glioma cell proliferation, invasion, and migration and altered the expression of oncogenic markers. These results conclusively demonstrated that PGC-1α plays a critical role in maintaining the malignant phenotype of glioma cells and indicated that targeting PGC-1α could be an effective strategy to curb glioma progression and improve patient survival outcomes.
PubMed: 38790941
DOI: 10.3390/biomedicines12050979 -
Molecular Biomedicine May 2024Carcinoembryonic antigen (CEA) is a tumor-associated antigen primarily produced by tumor cells. It has been implicated in various biological processes such as cell...
Carcinoembryonic antigen (CEA) is a tumor-associated antigen primarily produced by tumor cells. It has been implicated in various biological processes such as cell adhesion, proliferation, differentiation, and metastasis. Despite this, the precise molecular mechanisms through which CEA enhances tumor cell proliferation remain largely unclear. Our study demonstrates that CEA enhances the proliferation and migration of non-small cell lung cancer (NSCLC) while also inhibiting cisplatin-induced apoptosis in NSCLC cells. Treatment with CEA led to an increase in mitochondrial numbers and accumulation of lipid droplets in A549 and H1299 cells. Additionally, our findings indicate that CEA plays a role in regulating the fatty acid metabolism of NSCLC cells. Inhibiting fatty acid metabolism significantly reduced the CEA-mediated proliferation and migration of NSCLC cells. CEA influences fatty acid metabolism and the proliferation of NSCLC cells by activating the PGC-1α signaling pathway. This regulatory mechanism involves CEA increasing intracellular cAMP levels, which in turn activates PKA and upregulates PGC-1α. In NSCLC, inhibiting the PKA-PGC-1α signaling pathway reduces both fatty acid metabolism and the proliferation and migration induced by CEA, both in vitro and in vivo. These results suggest that CEA contributes to the promotion of proliferation and migration by modulating fatty acid metabolism. Targeting CEA or the PKA-PGC-1ɑ signaling pathway may offer a promising therapeutic approach for treating NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Carcinoembryonic Antigen; Lung Neoplasms; Cell Proliferation; Cell Line, Tumor; Cell Movement; Cyclic AMP-Dependent Protein Kinases; Animals; Signal Transduction; Disease Progression; Mice; Apoptosis; Fatty Acids
PubMed: 38782774
DOI: 10.1186/s43556-024-00181-3 -
Journal of Nanobiotechnology May 2024With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional...
With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional Chinese herb that can enhance the structure and function of muscles and bones. Otherwise, previous excellent publications illustrated that plant-derived exosome-like nanoparticles can exert good bioactive functions in different aging or disease models. Thus, we issued the hypothesis that Gouqi-derived nanovesicles (GqDNVs) may also have the ability to improve skeletal muscle health, though the effect and its mechanism need to be explored. Hence, we have extracted GqDNVs from fresh berries of Lycium barbarum L. (goji) and found that the contents of GqDNVs are rich in saccharides and lipids. Based on the pathway annotations and predictions in non-targeted metabolome analysis, GqDNVs are tightly associated with the pathways in metabolism. In muscle atrophy model mice, intramuscular injection of GqDNVs improves the cross-sectional area of the quadriceps muscle, grip strength and the AMPK/SIRT1/PGC1α pathway expression. After separately inhibiting AMPK or PGC1α in C2C12 cells with dexamethasone administration, we have found that the activated AMPK plays the chief role in improving cell proliferation induced by GqDNVs. Furthermore, the energy-targeted metabolome analysis in the quadriceps muscle demonstrates that the GqDNVs up-regulate the metabolism of amino sugar and nucleotide sugar, autophagy and oxidative phosphorylation process, which indicates the activation of muscle regeneration. Besides, the Spearman rank analysis shows close associations between the quality and function of skeletal muscle, metabolites and expression levels of AMPK and SIRT1. In this study, we provide a new founding that GqDNVs can improve the quality and function of skeletal muscle accompanying the activated AMPK/SIRT1/PGC1α signaling pathway. Therefore, GqDNVs have the effect of anti-aging skeletal muscle as a potential adjuvant or complementary method or idea in future therapy and research.
Topics: Animals; Sirtuin 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mice; Signal Transduction; Dexamethasone; AMP-Activated Protein Kinases; Muscular Atrophy; Cell Line; Drugs, Chinese Herbal; Male; Muscle, Skeletal; Mice, Inbred C57BL; Nanoparticles; Exosomes
PubMed: 38778385
DOI: 10.1186/s12951-024-02563-9 -
The Journal of Biological Chemistry May 2024As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic... (Review)
Review
As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.
PubMed: 38763333
DOI: 10.1016/j.jbc.2024.107388 -
Free Radical Biology & Medicine Aug 2024Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy...
Oxidative stress in peroxisomes induced by androgen receptor inhibition through peroxisome proliferator-activated receptor promotes enzalutamide resistance in prostate cancer.
Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.
Topics: Male; Humans; Phenylthiohydantoin; Nitriles; Peroxisomes; Oxidative Stress; Drug Resistance, Neoplasm; Benzamides; Receptors, Androgen; Reactive Oxygen Species; PPAR alpha; Cell Proliferation; Prostatic Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Signal Transduction; Androgen Receptor Antagonists; RNA, Small Interfering
PubMed: 38762061
DOI: 10.1016/j.freeradbiomed.2024.05.030 -
Poultry Science Apr 2024Previously, we reported that glucagon-like peptide-1 (GLP-1) and its analog liraglutide could inhibit fat de novo synthesis in the liver and reduce abdominal fat...
Previously, we reported that glucagon-like peptide-1 (GLP-1) and its analog liraglutide could inhibit fat de novo synthesis in the liver and reduce abdominal fat accumulation in broiler chickens. Nevertheless, the impact of GLP-1 on adipocyte fat deposition remains enigmatic. This study aimed to investigate the effects of GLP-1, via its analog liraglutide, on chicken chicken adipocytes in vitro. Chemical assays, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were employed to assess the proliferation, differentiation, and fat deposition of chicken adipocytes. Our findings indicated that liraglutide significantly suppressed cell proliferation and promoted preadipocyte differentiation in comparison to the control group. This was evidenced by elevated triglyceride (TG) content and upregulated mRNA expression of lipogenesis-related enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), as well as regulators including peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element binding protein-1 (SREBP1) and CCAAT/enhancer binding protein α (CEBPα). In mature adipocytes, liraglutide attenuated fat deposition by inhibiting fat de novo synthesis, evidenced by decreased mRNA expression of ACC, FAS, PPARγ, C/EBPα, and SREBP1, and concurrent upregulation of phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated ACC (p-ACC). This resulted in reduced accumulation of lipid droplets and TG content in mature adipocytes. Collectively, our findings indicate that liraglutide suppresses the proliferation of preadipocytes, enhances their differentiation, and concurrently inhibits de novo lipogenesis in mature adipocytes. This observation offers profound insights into the mechanisms that underlie liraglutide's anti-adipogenic effects, which could have significant implications for the treatment of obesity in broiler chickens.
PubMed: 38759567
DOI: 10.1016/j.psj.2024.103766 -
Scientific Reports May 2024Osteoarthritis (OA) is the most prevalent form of arthritis, characterized by a complex pathogenesis. One of the key factors contributing to its development is the...
Osteoarthritis (OA) is the most prevalent form of arthritis, characterized by a complex pathogenesis. One of the key factors contributing to its development is the apoptosis of chondrocytes triggered by oxidative stress. Involvement of peroxisome proliferator-activated receptor gamma (PPARγ) has been reported in the regulation of oxidative stress. However, there remains unclear mechanisms that through which PPARγ influences the pathogenesis of OA. The present study aims to delve into the role of PPARγ in chondrocytes apoptosis induced by oxidative stress in the context of OA. Primary human chondrocytes, both relatively normal and OA, were isolated and cultured for the following study. Various assessments were performed, including measurements of cell proliferation, viability and cytotoxicity. Additionally, we examined cell apoptosis, levels of reactive oxygen species (ROS), nitric oxide (NO), mitochondrial membrane potential (MMP) and cytochrome C release. We also evaluated the expression of related genes and proteins, such as collagen type II (Col2a1), aggrecan, inducible nitric oxide synthase (iNOS), caspase-9, caspase-3 and PPARγ. Compared with relatively normal cartilage, the expression of PPARγ in OA cartilage was down-regulated. The proliferation of OA chondrocytes decreased, accompanied by an increase in the apoptosis rate. Down-regulation of PPARγ expression in OA chondrocytes coincided with an up-regulation of iNOS expression, leading to increased secretion of NO, endogenous ROS production, and decrease of MMP levels. Furthermore, we observed the release of cytochrome C, elevated caspase-9 and caspase-3 activities, and reduction of the components of extracellular matrix (ECM) Col2a1 and aggrecan. Accordingly, utilization of GW1929 (PPARγ Agonists) or Z-DEVD-FMK (caspase-3 inhibitor) can protect chondrocytes from mitochondrial-related apoptosis and alleviate the progression of OA. During the progression of OA, excessive oxidative stress in chondrocytes leads to apoptosis and ECM degradation. Activation of PPARγ can postpone OA by down-regulating caspase-3-dependent mitochondrial apoptosis pathway.
Topics: Humans; Chondrocytes; PPAR gamma; Apoptosis; Caspase 3; Osteoarthritis; Mitochondria; Reactive Oxygen Species; Oxidative Stress; Membrane Potential, Mitochondrial; Cell Proliferation; Nitric Oxide; Cells, Cultured; Middle Aged; Aged; Female; Male
PubMed: 38755283
DOI: 10.1038/s41598-024-62116-w -
PloS One 2024The membrane peroxisomal proteins PEX11, play a crucial role in peroxisome proliferation by regulating elongation, membrane constriction, and fission of pre-existing...
The membrane peroxisomal proteins PEX11, play a crucial role in peroxisome proliferation by regulating elongation, membrane constriction, and fission of pre-existing peroxisomes. In this study, we evaluated the function of PEX11B gene in neural differentiation of human embryonic stem cell (hESC) by inducing shRNAi-mediated knockdown of PEX11B expression. Our results demonstrate that loss of PEX11B expression led to a significant decrease in the expression of peroxisomal-related genes including ACOX1, PMP70, PEX1, and PEX7, as well as neural tube-like structures and neuronal markers. Inhibition of SIRT1 using pharmacological agents counteracted the effects of PEX11B knockdown, resulting in a relative increase in PEX11B expression and an increase in differentiated neural tube-like structures. However, the neuroprotective effects of SIRT1 were eliminated by PPAR inhibition, indicating that PPARɣ may mediate the interaction between PEX11B and SIRT1. Our findings suggest that both SIRT1 and PPARɣ have neuroprotective effects, and also this study provides the first indication for a potential interaction between PEX11B, SIRT1, and PPARɣ during hESC neural differentiation.
Topics: Humans; Sirtuin 1; PPAR gamma; Cell Differentiation; Human Embryonic Stem Cells; Membrane Proteins; Neurons; Cell Line; Peroxisomes
PubMed: 38753762
DOI: 10.1371/journal.pone.0298274