Asia Pacific Academy of Science Pte. Ltd.
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Circular RNA ACTN4 (CircACTN4) Promotes Epithelial-Mesenchymal Transition and Angiogenesis in Gastric Cancer Cells
No full textBackground: Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in gastric cancer remains largely unknown. This research aimed to explore the key biological function, clinical relevance, and expression of the circular RNA ACTN4 (circACTN4) in gastric cancer. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine circACTN4 expression in gastric cancer cell lines and tissue samples. The effects of circACTN4 depletion or overexpression on the angiogenesis, migration, invasion, colony formation, and proliferation of gastric cancer cells were assessed by cell counting kit-8 (CCK-8), clonogenic assay, Transwell assay, and angiogenesis analyses. Western blot assay determined whether low or high levels of circACTN4 mRNA affected the expression of invasion- and angiogenesis-related proteins. Utilizing a tumorigenicity experiment in nude mice, the effect of circACTN4 inhibition on the ability of gastric cancer to proliferate in vivo was investigated. The effect of circACTN4 knockdown on the expression of the protein implicated in angiogenesis, migration, and proliferation in tumor-bearing tissues was investigated using immunohistochemistry. Results: Compared with para-carcinoma tissue and normal gastric epithelial cells, circACTN4 was upregulated in gastric cancer tissues (p < 0.01) and cell lines. CircACTN4 knockdown decreased gastric cancer cells proliferation (p < 0.01), migration (p < 0.05), and angiogenesis (p < 0.01), whereas circACTN4 overexpression had the opposite effect. The western blot showed that inhibiting circACTN4 substantially increased E-cadherin expression (p < 0.05) but decreased the expressions of Vimentin, N-cadherin, and Vascular Endothelial Growth Factor A (VEGFA) (p < 0.05). Knocking down circACTN4 in BALB/c mice significantly inhibited gastric cancer cell proliferation (p < 0.01), promoted E-cadherin expression, and suppressed Ki-67 (nuclear protein-67) and VEGFA expressions. Conclusions: In conclusion, the current research showed that circACTN4 functions as a tumor-promoting gene and is overexpressed in gastric cancer tissues and cells. Experiments conducted in vitro and in vivo showed that circACTN4 knockdown can greatly reduce angiogenesis, invasion, and proliferation of gastric cancer. Therefore, circACTN4 may be a molecular target in the treatment of gastric cancer
Effect of Flupentixol-Melitracen in Combination with Psychotherapy on Negative Mood, Psychological Stress and Life Quality in Coronary Heart Disease Patients Complicated with Psychological Disorders
No full textBackground: Coronary heart disease (CHD) is a common cardiovascular disease in clinical settings, which often combines with psychological disorders. Therefore, this study aimed to investigate the impact of flupentixol-melitracen in combination with psychotherapy on CHD patients complicated with psychological disorders. Methods: A total of 120 CHD patients with psychological disorders were divided into two groups: the control group (n = 60) and the observation group (n = 60). The patients in the former group received flupentixol-melitracen based on conventional therapy, while the latter group was additionally treated with psychotherapy on the basis of the control group. Moreover, before and after treatment, the depression and anxiety levels in patients were evaluated utilizing the scores of the Beck Depression Inventory (BDI), the Spielberg State-Trait Anxiety Inventory form 1 (STAI-state), and Spielberg State-Trait Anxiety Inventory form 2 (STAI-trait). Furthermore, the quality-of-life scoring was assessed using the questionnaire, and serum factor levels were determined by commercial kits. Results: Compared to the levels before treatment, the BDI, STAI-state, and STAI-trait scores, hypersensitive C-reactive protein (hs-CRP), lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB), and substance P (SP) were significantly decreased in both groups after treatment (p < 0.05). However, their levels were substantially alleviated in the observation group compared to the control group (p < 0.01). Furthermore, the interleukin-10 (IL-10) and 5-hydroxytryptamine (5-HT) levels were higher in the observation group compared to the control group (p < 0.001). After treatment, there were no abnormalities in blood pressure, blood and urine routine, and hepatorenal function in the two groups. Conclusion: Flupentixol-melitracen in combination with psychotherapy can relieve depression and anxiety in CHD patients with psychological disorders. Furthermore, this method can improve the inflammatory level and quality of life of patients
Molecular Mechanism of γδ1T-Derived IL-17D Promoting Malignant Biological Behavior of Breast Cancer through Activation of CD93/Cbl/Rho Molecular Axis
No full textObjective: In women, breast cancer (BC) is the most common malignant tumor, accounting for 7–10% of the incidence of various malignant tumor throughout the body. The purpose of this study was to investigate the role of γδ1T cells-derived interleukin (IL)-17D in BC and its molecular mechanism. Methods: The γδ1T cells were isolated from human BC tissues using magnetic beads and identified by flow cytometry. MDA-MB-231 cells or cells co-cultured with γδ1T cells were injected subcutaneously into nude mice at a dose of 5 × 106 cells/mouse to construct an animal model of BC. Enzyme-Linked Immunosorbent Assay (ELISA), Western blot, cell cloning, and scratch test were used to detect malignant biological behavior of BC cells. Observation of mammary carcinoma pathology in nude mice was conducted using hematoxylin-eosin (HE) staining. Results: In in vitro cell experiments, co-immunoprecipitation demonstrated the presence of binding relationships between IL-17D and CD93 as well as between Src and Casitas B-spectrum lymphoma (Cbl). γδ1T-derived IL-17D targeted activation of the breast cancer CD93 receptor and promoted Src-mediated phosphorylation of Cbl, which in turn induced Rho family activation, ultimately promoting MDA-MB-231 cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), enhancing the malignant biological behavior of BC cells. In in vivo experiments, γδ1T promoted an increase in tumor size, volume, and weight, as well as T-cell infiltration and ki-67 expression in cancerous tissues in nude mice, promoting EMT, and thus, malignant progression of BC. Conclusions: γδ1T-derived IL-17D promotes BC progression through activation of the CD93/Cbl/Rho molecular axis
mTORC1-ATF4-MCP-1 Pathway as a Driver of Chronic Thromboembolic Pulmonary Hypertension in Rats through the Induction of Endothelial Dysfunction and Pulmonary Artery Thromboembolism
No full textBackground: Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating condition caused by a putative mechanism associated with the activation of the mammalian target of rapamycin (mTOR). The current study aims to unravel the signaling pathway leading to CTEPH on the basis of mTOR activation. Methods: In vivo CTEPH models were established from rats exposed to repeated autologous thromboembolization. The rats were subjected to right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP) measurement as well as histopathological examination. To establish CTEPH cellular models for in vitro experiments, pulmonary artery endothelial cells were isolated from CTEPH rats and identified via immunofluorescence/flow cytometry. AZD8055, an mammalian target of rapamycin complex 1 (mTORC1) inhibitor, was used to treat both in vivo and in vitro models. Activating transcription factor 4 (ATF4) was overexpressed in in vitro models. Viability and apoptosis were detected using cell counting kit-8 assay and flow cytometry. Expression of mTOR, ATF4 and monocyte chemoattractant protein-1 (MCP-1) in pulmonary artery tissues/cells was measured by means of immunohistochemistry, Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). The interaction between ATF4 and MCP-1 was predicted with bioinformatics approach and validated using Chromatin immunoprecipitation (ChIP) assay. Results: CTEPH rats exhibited elevated mPAP, activated mTORC1-ATF4-MCP-1 pathway, increased area/total area of pulmonary artery, and enhanced apoptosis and thromboembolism in the pulmonary artery tissues, which were all reversed by AZD8055 treatment. In in vitro models, ATF4 overexpression decreased cell viability, enhanced apoptosis and upregulated MCP-1 level, while AZD8055 exerted an opposite effect, normalizing these changes and suppressing the mTORC1-ATF4-MCP-1 pathway. ATF4 could bind to MCP-1 promoter region. Conclusion: The mTORC1-ATF4-MCP-1 pathway induces endothelial dysfunction and pulmonary artery thromboembolism to promote the development of CTEPH in rats
Endocannabinoid System and Neuromodulation in Neurodegenerative Diseases: A Focus on Neuropsychiatric Symptoms
No full textBackground: Recent achievements in neurosciences have shown a growing interest in the role of endocannabinoid system (ECS) in the regulation of neuroprotection and neurodevelopment, with growing interest in the regulation of psychological processes. As well as neurotransmitters, endocannabinoids are molecules produced in our organisms and used as messengers in order to transmit signals between cells and activate responses, by interacting with several receptors. Recent studies have highlighted the involvement of the ECS in the physiopathology of several neurodegenerative disorders, such as Parkinsons Disease (PD), Alzheimers Disease (AD) and Huntington Disease (HD). Methods: We searched the PubMed/Medline, Scopus, Embase, and ScienceDirect databases on 1st September 2023, focusing on recent research regarding the role of endocannabinoids on the physiopathogenesis of neurodegenerative diseases with neuropsychiatric symptoms. We explored the role of ECS in the development of neurodegenerative disorders and the link to the onset of neuropsychiatric symptoms and future therapeutic strategies that implicate ECS activity in relation to these diseases. Results: There is a strong involvement of endocannabinoids in neurodegenerative diseases and psychiatric conditions, with growing evidences on efficacy of Cannabidiol (CBD)-based treatments. Conclusions: Recent ECS-mediated pathways have been found to be involved in neurodegenerative diseases and psychiatric conditions. CBD-based treatments may be promising neuropsychopharmacological interventions for psychiatric symptoms on AD, PD and HD patients, worthy of being further explored
Dysregulated Antioxidant Network and Increased iNOS Signaling in Platelets of Children with Autism Spectrum Disorder
No full textBackground: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the significant involvement of both environmental and immunological factors. The pathophysiology of ASD has been linked to dysregulation of the antioxidant network and production of oxidants in immune cells. Previous studies have demonstrated disequilibrium in different enzymatic antioxidants in the plasma, red blood cells, and leukocytes of individuals with ASD; however, there has been no investigation thus far into the evaluation of these antioxidants in peripheral platelets in both individuals with ASD and typically developing control (TDC) children. Methods: Given this context, we investigated the levels and functions of key enzymatic antioxidants in peripheral platelets of TDC (n = 23)/ASD (n = 26) individuals, including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TRxR) through flow cytometric and enzymatic activity analyses. Further, levels of oxidative stress were evaluated by analysis of inducible nitric oxide synthase (iNOS) and nitrotyrosine formation in the platelets of both groups. Results: Our findings reveal a marked reduction in SOD1 (p < 0.0001) and TRxR1 (p < 0.01) expression in the platelets of ASD individuals, as evidenced by diminished SOD1+ and TRxR1+ immunostaining in CD42+ cells. SOD (p < 0.01) and TRxR (p < 0.01) activity were also significantly lower in ASD participants compared to the TDC group. In contrast, when comparing individuals with ASD to TDC group, GPx/GR activity/expression in platelets is either decreased or unaffected. A notable increase in iNOS (p < 0.0001) coupled with reduced SOD/TRxR activity in ASD platelets correlated with a significant rise in nitrotyrosine expression (p < 0.001), indicative of oxidant damage. Conclusions: Our findings demonstrate, for the first time, that ASD individuals have a disrupted enzymatic antioxidant system and heightened oxidative stress in their peripheral platelets. This imbalance in enzymatic antioxidants may significantly impact the development of ASD and its associated comorbidities
FDFT1 Reduces Stemness and Autocrine/Juxtacrine Signaling in FOLFOX-resistant Colon Cancer Cells
No full textBackground: Colon cancer (CC) is a prevalent malignant tumor, that is widely treated with chemotherapy drug, such as 5-fluorouracil+oxaliplatin (FOLFOX). However, the emergence of FOLFOX resistance poses a significant challenge to its therapeutic efficacy. This study aimed to investigate the effect of farnesyl-diphosphate farnesyltransferase (FDFT1) on the progression of FOLFOX-resistant CC cells. Methods: The human CC cells, including HCT-116 and HT-29, were used in establishing a chemotherapy-resistant cell model by their exposure to FOLFOX. Furthermore, these cells were transfected with either FDFT1-overexpression plasmid or empty vector. The impact of FDFT1 expression on the FOLFOX-resistant CC cells was evaluated by assessing the levels of cancer stem cell markers using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analysis. Furthermore, the colony formation and the DNA damage/condensation were examined employing the colony forming assay and 4′,6-diamidino-2-phenylindole (DAPI) nuclei staining method, respectively. Moreover, western blot analysis was used to determine the levels of chemotherapy-resistance-related proteins, cell proliferation-related epidermal growth factor receptor (EGFR), and autocrine/juxtacrine pathway-related transforming growth factor alpha (TGF-α). Finally, the apoptosis rate in the transfected cells was assessed utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and flow cytometry. Results: The FDFT1 was downregulated in FOLFOX-resistant cells (p < 0.01) and cell transfection successfully upregulated FDFT1 in FOLFOX-resistant cells (p < 0.01). Furthermore, FDFT1 overexpression substantially reduced cancer stem cell markers (p < 0.01), inhibited tumor sphere formation (p < 0.01), increased DNA condensation (p < 0.001), and suppressed drug-related proteins (p < 0.001) in FOLFOX-resistant cells. Moreover, overexpression of FDFT1 suppressed the cell proliferation and reduced the activity of autocrine/juxtacrine signaling in FOLFOX-resistant cells by downregulating EGFR (p < 0.001) and TGF-α (p < 0.001). Additionally, FDFT1 increased apoptosis in FOLFOX-resistant cells when exposed to FOLFOX (p < 0.01). Conclusion: This study revealed an inhibitory role of FDFT1 in FOLFOX-resistant CC cells. Overexpression of FDFT1 can reduce cancer stem cell markers and inhibit tumor proliferation. Additionally, overexpression of FDFT1 suppressed the activity of autocrine/juxtacrine signaling, leading to increased cell apoptosis. These findings suggest FDFT1 as a potential therapeutic target and offer new insights for improving the efficacy of FOLFOX
Alteration of Spleen Macrophage Phenotypes Impacts Exosomes-Related Proteins in Gentamicin Toxicity Model
No full textBackground: Necroinflammation loop is a pathologic hallmark of organ dysfunction. That is owed to a distorted balance between the pro-inflammatory (M1) and the anti-inflammatory (M2) macrophages. We aimed to explore whether low-intensity pulsed ultrasound (LIPUS) and/or splenectomy could ameliorate necroinflammation by increasing M2 macrophages and modulating the exosomes-related proteins. Method: Rats were allocated into 2 groups: Sham and splenectomy (Splen). After that, rats were divided into LIPUS untreated and treated subgroups. Rats in each subgroup were subjected to either vehicle (sham, sham + LIPUS) or gentamicin (GM) (GM, GM + LIPUS, Splen + GM, Splen + GM + LIPUS). Biochemical and immunohistological analyses assessed macrophage polarization, necroptosis, exosomes-related markers, and exosomes-related proteins. Results: We found that LIPUS successfully reversed the effects of GM, LIPUS significantly-decreased (p < 0.05) necroinflammation markers through significant downshifting (p < 0.05) of M1 macrophage polarization, and noticeable modification (p < 0.05) of the exosome-related proteins (Milk fat globule-EGF factor 8 (MFG-E8), heat shock protein 70 (Hsp70)). Conclusion: Spleen could be a promising target for LIPUS via restoring M1/M2 balance and modulation of exosomes-related proteins
Fundamentals of Reductive Stress
Get PDFReductive stress is a cellular insult stemming from the overgeneration of reducing equivalents and heightened antioxidant potential within the body. Maintaining redox homeostasis necessitates a delicate balance between oxidant and antioxidant production. Key indicators of this balance include ratios such as Reduced glutathione (GSH) to Oxidized glutathione (GSSG), Nicotinamide adenine dinucleotide phosphate (NADP) to Reduced nicotinamide adenine dinucleotide phosphate (NADPH), and Nicotinamide adenine dinucleotide (NAD+) to Reduced nicotinamide adenine dinucleotide (NADH). Glutathione, an endogenous antioxidant, can also be supplemented through natural food sources such as okra, spinach, broccoli, and sweet potatoes among others. These reducing equivalents primarily stem from cellular metabolic processes such as the Krebs cycle and glycolysis. When present in excess, they can modulate signaling pathways, disrupt transcriptional activity, and reduce cellular metabolism, paving the way for various diseases. Conditions associated with reductive stress include cancer, protein aggregation cardiomyopathy, muscular dystrophy, and Alzheimers disease, among others. Moreover, prolonged use of antioxidant supplements like Vitamins and/or flavonoids may have pro-oxidant effects, disturbing cellular redox balance, inducing reductive stress, and potentially shortening life expectancy. Therefore, the consumption of antioxidant supplements should be moderate and appropriate, as excessive or haphazard intake can be detrimental to overall health
Stromal CXCL14 Promotes Cisplatin Resistance in Lung Adenocarcinoma by Activating ANGPTL4 Signaling Pathway
No full textBackground: Cisplatin-based therapy remains a critical treatment for patients with advanced lung adenocarcinoma (LUAD). However, the development of resistance to cisplatin hampers the sustained benefit to patients. Recent studies have shown that molecules secreted by stromal tissue play a pivotal role in tumor chemoresistance. This study aimed to validate the role of CXC-chemokine ligand 14 (CXCL14), a stromal-secreted molecule, and its functional mechanism in cisplatin resistance. Methods: We analyzed The Cancer Genome Atlas (TCGA) database using bioinformatics methods, leading to the selection of CXCL14 for validation on a LUAD tissue microarray (TMA) of 120 patients. The protein expression of CXCL14 was assessed through immunohistochemistry (IHC). A549 and H3255 cells were cultured in two-dimensional (2D) or three-dimensional (3D) patterns. In this study, we evaluated cell viability, cell apoptosis and death, molecular expression, signaling pathways, and xenograft growth using in vitro methods such as Cell Counting Kit-8 (CCK8) assays, colony formation assays, flow cytometry, cell live/dead double staining, quantitative PCR, Western blot, RNA sequencing, and in vivo mouse tumor-bearing models. Results: CXCL14 was found to be highly expressed in the stroma of lung adenocarcinoma in both the TCGA training cohort and the TMA validation cohort, suggesting its potential role in the interaction between stromal and tumor cells. Cisplatin inhibited cell viability, induced cell apoptosis in 2D or 3D cultured A549 and H3255 cells in vitro, and suppressed tumor growth in vivo. These effects were significantly alleviated by adding CXCL14. Further investigation revealed that CXCL14 promoted cisplatin resistance by upregulating Angiopoietin Like Protein 4 (ANGPTL4), activating the downstream extracellular regulated protein kinases (ERK) signaling pathways. Conclusion: CXCL14, a stromal marker, promotes cisplatin resistance in LUAD by activating ANGPTL4 and the downstream ERK signaling pathway. Identifying the downstream effectors, or the use of neutralizing/non-neutralizing antibodies targeting this pathway may provide valuable insights and serve as a reference for developing strategies to effectively control cisplatin resistance, a topic that warrants further investigation