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CIRBP Promotes Colorectal Cancer Progression by Regulating SAM68/p38 Signaling Pathway
No full textBackground: Colorectal cancer (CRC) is a type of malignant gastrointestinal cancer with a poor prognosis. Cold-inducible RNA binding protein (CIRBP) is a novel proto-oncogene that promotes the development of certain malignancies. Nevertheless, the relevance of CIRBP in CRC and the molecular processes behind it are still unknown. This study aimed to explore the molecular mechanism and biological function of CIRBP in CRC. Methods: In this study, CIRBP protein expression in CRC samples and control samples was analyzed by Immunohistochemistry (IHC) analysis. The relationship of CIRBP expression and disease-free survival (DFS) and overall survival (OS) was assessed in CRC patients. Immunofluorescence (IF) assay, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze the expression or connection of CIRBP and Src associated in mitosis of 68 kDa (sarcoma-associated in mitosis of 68 kDa (SAM68)). CRC proliferation was investigated by cell-counting-kit-8 (CCK8) assay, colony formation assay, flow cytometric analysis, and animal studies. Migration and invasion were investigated by transwell assay. RNA sequencing and Common-immunoprecipitation (Co-IP) with protein mass spectrometry were used to investigate the underlying pathways of CIRBP in CRC. Results: The findings demonstrated that CIRBP was abundant in CRC tissues, and that individuals with significant CIRBP expression had a poor prognosis. In vitro and in vivo, CIRBP/SAM68 knockdown or overexpression reduced or accelerated CRC proliferation, invasion and migration, respectively. Moreover, overexpression of SAM68 rescued the influence of CIRBP silencing on the malignant phenotype. Mechanistically, CIRBP directly bound to and increased the expression of SAM68. This mediated the excessive activation of the p38 signaling pathway. Overall, this study showed that CIRBP was an upregulated CRC-related oncogene. Conclusion: Higher CIRBP expression may be related to decreased prognostic factors for overall survival (OS) and disease-free survival (DFS). CIRBP was found to enhance CRC development via the SAM68/p38 signal transduction pathway
Oridonin Improves Inflammatory Damage of Endothelial Cells in Kawasaki Disease via Regulating PADI2 Gene
No full textBackground: Kawasaki disease (KD) is a common multi-system vascular inflammatory disease in childhood. The main complication is coronary artery lesions (CALs). Despite its widespread prevalence, the precise pathogenesis of KD remains unknown. The purpose of this study is to investigate the potential therapeutic role and mechanism of Oridonin (Ori) in improving vascular endothelial cell injury in KD. Methods: The synthetic biotin coupled with Ori pulls down lysate protein products from Human umbilical vein endothelial cells (HUVECs). Subsequently, the pull-down proteins were detected using Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS), and bioinformatics analysis was utilized to screen for the key Ori binding protein Peptidylarginine Deiminase 2 (PADI2). HUVECs were then pretreated with various concentrations of Ori, including 0.5 μM, 1.0 μM, and 2.0 μM. The monocytic leukemia cell line (THP1) was treated with 15% serum obtained from KD patients and co-cultured with HUVECs to reconstruct the inflammatory environment of endothelial cells in KD. Moreover, by constructing the PADI2 interference plasmid for cell regulation experiments and in vivo experiments on mice injected with lactobacillus casei cell wall extract (LCWE) solution, the underlying mechanism of Ori treatment against KD was determined using Cell Counting Kit-8 (CCK-8), flow cytometry, Enzyme-Linked Immunosorbent Assay (ELISA), quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), and Western blot techniques. Results: The key Ori binding protein PADI2 was screened using LC-MS/MS detection of Ori pull-down proteins. Ori therapy improves KD-induced endothelial cell inflammatory damage, as evidenced by increased cell viability, reduced apoptosis, and decreased levels of pro-inflammatory cytokines like Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor necrosis factor-α (TNF-α) (p < 0.05). Additionally, Ori greatly reduced the expression of PADI2, phosphorylated NF-kappaB p65 (p-p65), and phosphorylated inhibitor of nuclear factor-kappa B (NF-κB) (phosphorylated inhibitor of NF-κB (p-IκB)) in HUVECs (p < 0.05). Ori demonstrated the optimum efficiency at 2 μM concentration (p < 0.05). Interfering with PADI2 markedly increased KD-induced HUVEC cell viability and inhibited apoptosis (p < 0.01). This interference also reduced the levels of IL-1β, TNF-α, and IL-6 along with downregulating the expression of PADI2, p-p65, and p-IκB (p < 0.01). The results of in vivo experiments revealed that both Ori and interfering with PADI2 alleviated coronary endothelial cell injury and inflammation. They also significantly elevated Nitric Oxide (NO) levels (p < 0.01), and significantly reduced endothelin (ET)-1 and pro-inflammatory cytokine levels (p < 0.01), as well as the expression of p-p65 and p-IκB in coronary tissue of mice (p < 0.01). Interference with PADI2 based on Ori stimulation significantly reduced p-p65 and p-IκB expression (p < 0.01). Conclusions: Ori exhibited the ability to improve the inflammatory damage of endothelial cells in KD by regulating the expression and viability of PADI2 to affect the activation of the NF-κB pathway and nuclear transport
Coixol Ameliorates Rheumatoid Arthritis by Regulating Macrophage Polarization by Suppressing the TLR4/NF-κB Pathway
Get PDFBackground: Coixol (COI) is derived from C. lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf and has been shown with protective effects on rheumatoid arthritis (RA). However, the detailed mechanisms of COI on RA remain unknown. The current study aimed to assess the therapeutic effect and possible mechanism of COI on RA. Methods: A collagen-induced arthritis (CIA) rat model was established, and COI was administered to CIA rats orally. The therapeutic effects of COI on RA were assessed based on arthritis score and paw volume, pathological staining and the levels of inflammatory factors. Then, the effects of COI on M1 macrophages (Mφ) polarization were evaluated through measuring the levels of M1Mφ-related factors, detecting the proportion of M1Mφ in spleen and synovium. Furthermore, the inhibitory effect of COI on M1Mφ polarization was verified in vitro and the changes in toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-κB) pathway in M1Mφ after COI treatment was evaluated through detecting the related levels of proteins and genes. Additionally, the inhibitory effect of COI on NF-κB p65 activation in M1Mφ was assessed through detecting the nucleus transition of NF-κB p65 and the NF-κB transcriptional activity. Results: COI decreased arthritis score and paw volume, improved the pathological changes, and reduced the levels of inflammatory factors in CIA rats (p < 0.01). Besides, COI treatment reduced the proportion of M1Mφ in the spleen and synovium (p < 0.01). In vitro studies suggested that COI decreased the proportion of M1Mφ and reduced the production of pro-inflammatory cytokines (p < 0.05, p < 0.01, respectively). Besides, COI treatment lowered the protein levels of TLR4/NF-κB pathway-related factors and downregulated the gene expression of downstream cytokines (p < 0.05, p < 0.01, respectively). Furthermore, COI treatment inhibited the nucleus transition of NF-κB p65 and diminished the transcriptional activity of NF-κB (p < 0.05). Conclusions: COI exhibits a significant therapeutic effect on RA. The anti-inflammatory mechanism of COI on RA is associated with inhibiting TLR4/NF-κB-mediated M1Mφ polarization
Polyunsaturated Fatty Acid Supplementation in Athletes: A Systematic Review
Get PDFBackground: This study aims to summarize the evidence regarding the effects of polyunsaturated fatty acids (PUFAs) supplementation on both amateur and professional athletes. Objective: The aim is to elucidate the impacts of PUFAs supplementation on physical performance, inflammatory response, biochemical profile, anthropometric/body composition, and performance outcomes in athletes. Methods: Articles published up to December 2023 were retrieved from databases including Cochrane Library, PubMed/Medline, Scopus, and Embase. Selected articles met eligibility criteria and quality methodology. Data on inflammatory response, biochemical markers, anthropometric/body composition, and neuromuscular indicators were extracted. Results: Twenty-one studies were included in this systematic review. PUFAs supplementation resulted in decreased levels of certain inflammatory markers (interferon-gamma, interleukin 1, prostaglandin E2, and tumor necrosis factor alpha). However, no significant differences were observed in interleukin 4, 6, 8, 10, and matrix metalloproteinase 9. Additionally, there were no differences in glycemic (glucose and insulin) and lipid metabolism (high density lipoprotein (HDL)) cholesterol, low density lipoprotein (LDL), triglycerides). A reduction in reactive oxygen species levels was noted. No significant differences were found in muscle fatigue markers and anthropometry. Some performance parameters (neuromuscular and aerobic) improved following supplementation, including performance on the Yo-Yo distance test, resting energy expenditure, exercise time to exhaustion, and maximum oxygen consumption/maximum heart rate. Conclusion: Supplementation with PUFAs (600–3150 mg) in athletes led to reductions in inflammation and oxidative stress markers, as well as improvements in specific aerobic performance parameters. However, no significant effects were observed on glycemic and lipid profiles, anthropometric profiles, or body composition
TFDP1 Enhances the Malignant Biological Behaviors of Breast Cancer Cells by Promoting ASF1B-mediated CKS1B Upregulation
No full textBackground: Overexpression of the transcription factor Dp-1 (TFDP1) has been demonstrated in breast cancer (BC), indicating a possible involvement in the progression of BC. This study explored the downstream mechanism of TFDP1 in BC. Methods: Quantification of TFDP1, anti-silencing function 1B histone chaperone (ASF1B) and CDC28 protein kinase regulatory subunit 1B (CKS1B) in BC cells was realized through quantitative real-time polymerase chain reaction (qRT-PCR). The relationship among TFDP1, ASF1B and CKS1B was predicted by GEPIA and verified by qRT-PCR and western blot. Through loss- and gain-of-function assays and rescue assays, the effects of TFDP1 and TFDP1/ASF1B/CKS1B axis upon viability, proliferation, migration, and invasion of BC cells were studied. Proliferating cell nuclear antigen (PCNA), matrix metalloproteinases (MMPs) and vimentin protein levels were determined by western blot. Results: TFDP1, ASF1B and CKS1B were highly expressed in BC and were positively correlated in pairs (p < 0.001). TFDP1 overexpression and ASF1B overexpression enhanced while TFDP1/CKS1B/ASF1B silencing suppressed the viability, migration, and invasion of BC cells, and TFDP1 silencing, CKS1B silencing or ASF1B silencing suppressed BC cell viability, migration, and invasion (p < 0.05). TFDP1 silencing suppressed CKS1B and ASF1B expressions (p < 0.05). ASF1B overexpression increased CKS1B, PCNA, MMP-2, MMP-9 and vimentin expression, while these effects were reversed by CKS1B silencing (p < 0.001). Conclusion: TFDP1 facilitates the malignant biological behaviors of BC cells by promoting ASF1B-mediated CKS1B upregulation
A Comprehensive In Silico Study of the NDB-IL-24 Fusion Protein for Tumor Targeting: A Promising Anti-Cancer Therapeutic Candidate
No full textBackground: Breast cancer remains a pervasive global health concern among women, with conventional therapies such as chemotherapeutic agents, radiography, and surgery lacking selectivity and causing undesirable side effects. In response to this challenge, fusion proteins are emerging as a promising avenue for targeted cancer therapy. This study aimed at in silico design of a chimeric protein by fusing the cell-penetrating peptide, nemo binding domain (NBD) peptide, with the cell-targeting peptide, interleukin 24 (IL-24), using linkers of varying lengths. The selected bifunctional peptide was investigated for its potential of enhanced anti-tumor activity through in silico methods. Methods: The 3D structure of the fusion peptide was initially modeled using I-TASSER (Iterative Threading Assembly Refinement) and AlphaFold2. The predicted structures underwent rigorous quality check and validation through Ramachandran plot analysis, ERRAT, and VERIFY 3D. The best model was refined, and physiochemical properties were evaluated. Subsequently, docking analysis was performed using ClusPro 2.0, and molecular dynamic simulations were performed using NAMD with VMD. Results: The results demonstrated a valid 3D structure with high model quality. The docked complex exhibited stability with 23 salt bridges, 17 hydrogen bonds, and 236 non-bonded contacts, suggesting a successful interaction of the fusion peptide with its potential receptor, thereby generating an apoptotic signal. Molecular dynamic simulations further confirmed the stability, flexibility, and functionality of the fusion protein, indicated by non-significant fluctuations in the generated graphs. Conclusion: In conclusion, our newly designed peptide holds promise as a potential drug candidate against breast cancer, warranting further evaluation through in vitro studies. Computational tools for designing such fusion proteins have proven valuable as an initial step preceding in vitro production
MGLL Coordinates YWHAZ to Mediate Gemcitabine Resistance in Pancreatic Cancer via IL6/PI3K/AKT Signaling Pathway
No full textBackground: The frequency of neoplastic disorders, pancreatic ductal adenocarcinoma (PDAC), is increasing annually. PDAC is an aggressive cancer and can be partly managed with systemic chemotherapy, as it is usually diagnosed at advanced stages. Unfortunately, only 23.8% PDAC patients are clinically sensitive to gemcitabine (GEM) treatment. Therefore, this study aimed to understand the etiology and pathobiology of chemoresistance in PDAC, deciphering the molecular mechanisms underlying PDAC progression. Methods: The expression levels of two important genes were investigated in the clinical tissues samples of gemcitabine-sensitive and gemcitabine-resistant PDAC patients. Furthermore, lentivirus was used to knock down and overexpress target genes, and RNA sequencing was utilized to further investigate the downstream regulators. Additionally, plate cloning, flow cytometry, and in vivo tumorigenicity were used to demonstrate the involvement of these key genes in gemcitabine resistance in PDAC. Eventually, the downstream regulators of gemcitabine resistance of PDAC was assessed using western blot (WB) and enzyme-linked immunosorbent assay (ELISA), respectively, aiming to evaluate the impacts of phosphatidylinositol 3-kinase and protein kinase B (PI3K/AKT) pathway-related proteins and Interleukin 6 (IL6) inflammatory factor. Results: The expressions of monoacylglycerol lipase (MGLL) and Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) were higher in gemcitabine-resistant PDAC patients than in gemcitabine-sensitive PDAC patients (p < 0.05). In vitro experiments revealed that both overexpression and silencing of these genes altered the capacity to establish gemcitabine resistance (p < 0.05). RNA sequencing results indicated that these two genes combinedly regulate the expression of IL6 and demonstrated that they regulate drug resistance by activating the PI3K/AKT signaling pathway (p < 0.05). Moreover, in vivo experiments validated the involvement of MGLL and YWHAZ in improving gemcitabine resistance in pancreatic cancer (p < 0.05). Conclusions: This study demonstrates that MGLL and YWHAZ co-regulate the resistance to gemcitabine via the IL6/PI3K/AKT axis in PDAC. Therefore, MGLL/YWHAZ is a promising therapeutic target for the treatment of PDAC
Dexmedetomidine Alleviates Neuroinflammation-Induced Cognitive Impairment by Modulating the NLRP3 Inflammasome Activation Pathway
Get PDFObjective: Neuroinflammation-induced cognitive dysfunction (NICD) relies on symptomatic treatment, with no causative treatment strategies available yet. Therefore, comprehensive investigations on the pathogenesis of NICD are crucial for the development of novel and effective therapeutic drugs. Hence, we aimed to elucidate the impact of Dexmedetomidine (Dex) in modulating nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing-3 (NLRP3) inflammatory vesicles for improving cognitive dysfunction. Methods: The study employed both cellular and animal models. The HT22 cells were utilized to assess the impact of Dex on Lipopolysaccharide (LPS)-induced neuroinflammation. Cell viability was examined using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and changes in mitochondrial membrane potential were evaluated using the JC-1 kit. Furthermore, the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and NLRP3 were analyzed using Enzyme-Linked Immunosorbnent Assay (ELISA) and qPCR techniques. Additionally, NICD was induced in mice using LPS, and cognitive functions were assessed through the Morris water maze experiment. The expression levels of inflammatory markers in the hippocampal tissues of the mice were evaluated using the qPCR method. Results: The Dex treatment was found to restore the LPS-induced reduction in HT22 cell viability (p < 0.05), as well as significantly reduced the cellular levels of TNF-α, IL-1β, IL-6, and NLRP3 (p < 0.05). Furthermore, Dex treatment restored the mitochondrial membrane potential of HT22 cells (p < 0.05). Additionally, we observed that Dex treatment significantly improved the declining cognitive ability of NICD mice (p < 0.05). Conclusion: Dex can protect the learning and memory capabilities of cognitively impaired mice by inhibiting the expression of NLRP3 inflammatory vesicles as well as inflammatory factors
PDSS2 Methylation Exacerbates Heart Failure through Inhibition of the CXCL14/NF-κB Signaling Pathway
Get PDFBackground: Numerous reports have suggested a correlation between the occurrence of heart failure (HF) and the methylation status of specific key genes in myocardial cells. This study aimed to elucidate the mechanistic role and functional impact of the methylation of pentenyl diphosphate synthase subunit 2 (PDSS2) methylation in HF, offering insights for novel therapeutic approaches in HF management. Methods: The HF rat model was established via surgical intervention to explore the in vivo exacerbation of HF by PDSS2 methylation. Cardiac ultrasound and morphological assessments were used to evaluate HF in rat hearts. Hematoxylin-eosin (HE) staining was used to assess cardiac injury. The levels of PDSS2 methylation and expression were quantified, and the underlying mechanisms of PDSS2 in HF pathogenesis were explored. Results: Our findings revealed a significant reduction in PDSS2 levels in the heart tissue of HF rats (p < 0.05), concurrent with a notable increase in PDSS2 methylation (p < 0.05). Decreased PDSS2 methylation led to the upregulation of nuclear factor-kappaB (NF-κB) expression (p < 0.05) and chemokine (C-X-C motif) ligand 14 (CXCL14) levels (p < 0.05), consequently attenuating myocardial tissue damage in HF rats. However, silencing CXCL14 or administering the NF-κB inhibitor BAY 11-7082 reversed the protective effects of 5-Aza-2′-deoxycytidine (5-Aza) (p < 0.05), thus increasing myocardial tissue damage in HF rats. Conclusion: PDSS2 methylation is a significant contributor to cardiac dysfunction and the progression to heart failure, underscoring its potential importance in the therapeutic landscape of HF
Immune Effector Cell-Associated Neurotoxicity Syndrome of Chimeric Antigen Receptor T Cells: From Pathophysiology to Clinical Management
No full textChimeric antigen receptor (CAR)-T cell therapy has recently demonstrated promising outcomes for patients with malignant hematologic disorders. However, a significant number of these patients undergoing CAR-T cell therapy often present with symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS), a common reason for their hospitalization and need for intensive care, thereby impacting the broader application of this therapy. The early detection of neurological symptoms, identification of specific biomarkers, and effective handling of ICANS are crucial for optimizing the efficacy of CAR-T cell therapy. This review delves into the underlying mechanisms of ICANS, the initial recognition of its clinical indicators, and the strategies for its clinical management