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Aspirin Combined with Curcumin on Lgr5 Signaling Pathway Model of Colorectal Cancer through Warburg Effect by TAp63α Ubiquitination
No full textBackground: The changing lifestyles and dietary patterns in recent years have led to an increased incidence rate of colorectal cancer, posing a significant threat to the well-being and safety of patients. Therefore, the objective of this study was to investigate the therapeutic efficacy of the combination treatment of Aspirin and curcumin in a colorectal cancer model. The aim is to provide insights into potential approaches for managing this disease. Methods: All mice were randomly assigned to different groups, including sham, dextran sulphate sodium (DSS) + azoxymethane (AOM), Aspirin, Curcumin, and Union group, with six mice in each group. In vitro experiments utilized the human colon adenocarcinoma cell lines (HCT-116) as a model. For HCT-116 cells, TAp63alpha (TAp63α), si-TAp63α, negative control, or si-negative were transfected using Lipofectamine 2000, with three replicates per group. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression levels of Lrg5 and TAp63α after treatment with Aspirin combined with curcumin, both in vivo and in vitro. The Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-2-deoxyuridine (EDU) staining were used to evaluate the proliferation of colorectal cancer cells following combination treatment. Results: The combination treatment of Aspirin and curcumin resulted in a significant reduction in tumor numbers and tumor size in the colorectal cancer mouse model (p < 0.05). Moreover, this combination treatment led to reduced mRNA expressions of interleukin-6 (IL-6), IL-17α, and Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) in the tumor tissue of the mouse model (p < 0.05). In HCT-116 cells, the combination treatment of Aspirin and curcumin demonstrated inhibitory effects on cell proliferation and migration rates. It also reduced the rate of EDU-positive cells and increased Caspase-3/9 activity levels (p < 0.05). Additionally, this combination treatment resulted in decreased glucose consumption, lactate production, and adenosine triphosphate (ATP) quantity in HCT-116 cells (p < 0.05). Furthermore, it reduced extracellular acidification rate and increased oxygen consumption relative to basal levels (OCR, oxygen consumption rate) in HCT-116 cells (p < 0.05). The combination treatment of Aspirin and curcumin suppressed the mRNA expressions of TAp63α and Lgr5 in both the mouse model and in vitro models (p < 0.05). It also downregulated the protein expressions of TAp63α, Lgr5, and p-β-catenin in both models (p < 0.05). Notably, Aspirin had no effect on TAp63α ubiquitination, while curcumin promoted TAp63α ubiquitination in HCT-116 cells. Furthermore, compared to curcumin alone, the combination treatment of Aspirin and curcumin further enhanced TAp63α ubiquitination in HCT-116 cells (p < 0.05). The regulation of TAp63α played a crucial role in mediating the effects of Aspirin combined with curcumin on colorectal cancer cell growth and the progression of the Warburg effect. Conclusions: The combination treatment of Aspirin and curcumin effectively suppresses the proliferation and migration of colorectal cancer cells both in vitro and in vivo by targeting the Warburg effect. This modulation of the Warburg effect is mediated through the TAp63a/Lgr5 signaling pathway. These findings highlight the potential therapeutic value of Aspirin combined with curcumin for the treatment of colorectal cancer
Hypermethylation of SOCS3 Affects the Prognosis of Children with Acute Lymphoblastic Leukemia and is Reversed by 5-aza-2′-deoxycytidine Through Inhibiting Cell Proliferation and Increasing Cell Apoptosis
No full textBackground: Hypermethylation of the suppressor of cytokine signaling 3 (SOCS3) promoter has been found in most malignant tumors, but the correlation between acute lymphoblastic leukemia (ALL) and SOCS3 methylation has rarely been explored. Here, we mainly explored the role of SOCS3 methylation in ALL disease progression. Methods: Children with ALL were divided into low-level and high-level groups according to the methylation level of the SOCS3 gene. The logistic regression model was used to analyze the relationship between SOCS3 gene methylation level and the prognosis of ALL. Kaplan-Meier analysis was employed to assess overall survival (OS) and cumulative incidence of relapse (CIR). Bisulfite sequencing polymerase chain reaction (PCR) and flow cytometry were used to detect the changes in methylation level of the SOCS3 gene, and analyze the cell cycle and apoptosis in ALL cell lines before and after treatment with a methylase inhibitor. The Cell Counting Kit-8 assay and western blotting were used to detect the changes in cell proliferation and the protein expression levels of SOCS3, cleaved caspase-3, and p53 upregulated modulator of apoptosis (PUMA). Results: The methylation rate of the SOCS3 gene was 20.7% in the newly diagnosed group, 31.0% in the relapse group, 15.0% in the complete remission group, and almost nonexistent in the control group. Univariate Cox regression analysis showed that the high level of SOCS3 gene methylation was significantly associated with OS. The CIR in the high level group was significantly higher than that in the low-level group. After demethylation treatment, SOCS3 gene expression was significantly upregulated in ALL cells. Demethylation significantly inhibited the proliferation and arrested the cell cycle in the gap (G)0/G1 phase of ALL cells. SOCS3 demethylation may promote cell apoptosis by inducing the expression of apoptosis-related proteins such as cleaved caspase 3 and PUMA. Conclusions: The results of our study indicate that the level of SOCS3 methylation differs in patients with different stages of ALL, and is related to the relapse rate. SOCS3 methylation can be used as one of the early diagnostic and prognostic indicators of ALL. In ALL cells, SOCS3 demethylation significantly inhibited cell proliferation and viability. Thus, regulating the methylation status of SOCS3 gene may provide a new approach for the treatment of ALL. Clinical Trial Registration: This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706
Therapeutic Efficacy of Digoxin in Oxaliplatin and Chronic Constriction Injury Model of Neuropathic Pain in Rats
No full textBackground: Neuropathic pain poses a considerable challenge in clinical practice, affecting a significant portion of the global population. Existing treatments often provide only symptomatic relief and are associated with limited efficacy and adverse effects, highlighting the need for novel therapeutic strategies. Methods: This study investigates the repurposing potential of digoxin for neuropathic pain management. Digoxin works as a soluble epoxide hydrolase (sEH) enzyme inhibitor, traditionally given for cardiac conditions. The neuropathic pain management (anti-nociceptive and anti-inflammatory role) of digoxin at 0.1 & 0.2 mg/kg was studied in a rat model having chronic constriction injury (CCI) and oxaliplatin-induced neuropathy. The reduction in pain was assessed through multiple behavioural assays like the acetone drop test, hot plate test, and pin-prick test. The mitochondrial functions, oxidative stress, & inflammation condition were estimated by biochemical analyses & gene expression studies of relevant markers. The histopathological examination depicts the morphology of tissue damage. Results: Digoxin administration attenuated neuropathic pain behaviour and reduced neuroinflammation in both CCI and oxaliplatin-induced models. Additionally, digoxin treatment significantly improved mitochondrial function and decreased oxidative stress levels in rat models. Histopathological analysis revealed a reduction in axonal damage in the sciatic nerve. Gene expression analysis indicates downregulation of pro-inflammatory markers such as tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB). Conclusion: This study concludes that digoxin acts as a sEH inhibitor and holds promise for repurposing for neuropathic pain management
Esculentoside A Inhibits Lung Cancer Cell Migration and Invasion by Modulating Macrophage Polarization through IL-6/STAT3 Signaling Pathway
No full textBackground: Tumor-associated macrophage (TAM) is pivotal in cancer progression. Esculentoside A (EsA) is a saponin extracted from plants, which has anti-cancer and anti-inflammatory effects. However, its anti-cancer effects through inhibiting TAM activation are still unclear and need further research. Methods: Human myeloid leukemia mononuclear cells (THP-1) differentiate into M2 macrophages under induction. The cultivation of A549 and H1299 cells was performed in a conditioned medium from M2 macrophages (M2-CM) to fathom the effects of EsA on viability of cancer cells and their abilities to migrate and invade. The macrophage markers were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. Investigations on how EsA impacts interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway were conducted by means of western blot and immunofluorescence. Results: Adherent and rounded THP-1 cells were observed through propidium monoazide (PMA) treatment. THP-1 cells expressed M1 macrophage markers with induction of lipopolysaccharide/interferon-γ and expressed M2 macrophage markers after induction of IL-13/IL-4 (p < 0.01). EsA may dampen IL-13/IL-4-induced M2 macrophage polarization as indicated by downregulation of the mRNA levels of CD206 (M2 macrophage marker) and peroxisome proliferator-activated receptor γ (PPARγ) (p < 0.001), and inhibit IL-6 expression in cells and STAT3 phosphorylation (p < 0.05). Moreover, EsA reversed M2-CM-induced promotion of lung cancer cell migration and invasion (p < 0.05). Conclusions: EsA inhibits lung cancer cell migration and invasion by mediating macrophage polarization through IL-6/STAT3 signaling pathway
Human Plasma Protein Cocktail Decreases Burn Wound Expansion and Bacterial Growth
No full textBackground: Burn injuries lead to hemolysis and inflammation, simultaneously releasing reactive oxygen species (ROS) and toxic extracellular components such as hemoglobin, heme, and iron. Although the body naturally counteracts this toxicity by increasing the production of plasma scavenger proteins such as haptoglobin (Hp), hemopexin (Hpx), and transferrin (Tf), this protective response takes several hours to reach its peak. In the case of more severe burns, these plasma proteins may be depleted. Iron also serves as a nutrient for growing pathogens, potentially leading to subsequent infection. Methods: We tested the effect of a human plasma protein cocktail consisting of Hp, Hpx, and Tf on hydrogen peroxide (H2O2)-induced ROS injury in vitro and a burn injury mouse model of full-thickness wounds using different delivery routes of the protein cocktail. In addition, the antibacterial properties of the protein cocktail were assessed against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). Results: Metabolic activity of human fibroblasts decreased significantly after 1000 μM of H2O2 treatment for 24 hours, while the protein cocktail significantly reversed this effect in a dose-dependent manner. In the burn injury animal model, after 3 days, wound expansion and iron deposition were significantly reduced via daily treatment with the protein cocktail. This further led to better and more complete wound healing in these mice. Histologically, burn wounds were not entirely closed in the control group, unlike protein cocktail-treated wounds. Therefore, wound width was significantly larger in the control group. In bacterial zone inhibition assays against P. aeruginosa and S. aureus, the protein cocktail had minimal effect on bacterial inhibition when used alone; however, the protein cocktail, when used in conjunction with minimum doses of gentamicin, inhibited bacterial growth significantly. Conclusions: Using the scavenger plasma protein cocktail may reduce ROS injury, wound expansion, and bacterial growth in both in vitro and in vivo burn injury models. This approach could be potentially used in infected bacterial burn injury animal models and sets the stage for future application in burn injury patients for wound management and promotion of healing
The Knockdown of FKBP Prolyl Isomerase 10 (FKBP10) Reverses Resistance in BRAFV600E Mutant Thyroid Papillary Cancer Cells
No full textBackground and Objective: Vemurafenib (VEM) is commonly used to treat papillary thyroid cancer (PTC) with the B-Raf proto-oncogene, serine/threonine kinase (BRAF)V600E mutation. However, a major challenge during treatment is the emergence of cellular resistance to vemurafenib. Furthermore, FKBP Prolyl Isomerase 10 (FKBP10) has been associated with the occurrence and progression of various cancer types. Therefore, the current study aimed to investigate the role of FKBP10 in the emergence of cellular resistance to vemurafenib within PTC patients. Methods: The potential of FKBP10 in the proliferation of VEM-resistant cells was assessed in vitro using the Cell Counting Kit-8 (CCK-8), colony formation, and cell migration assays. Western blotting, Co-Immunoprecipitation, Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), and confocal immunofluorescence labeling assay were employed to investigate the underlying molecular mechanism of FKBP10 overexpression in VEM-resistant cells. Results: Compared to Nthy-ori 3-1, expression levels of FKBP10 were substantially increased in PTC cells. Furthermore, the knockdown of FKBP10 significantly increased their drug sensitivity. However, resistant cell lines exhibited a significant reduction in cell survival, migration, and colony formation (p < 0.05) and elevated apoptotic rate. Additionally, silencing FKBP10 (sh-FKBP10) significantly decreased the expression levels of p-Protein kinase B (AKT) and p-Phosphoinositide 3-kinase (pI3K) in human thyroid cancer papillary cells (p < 0.05). Similarly, treatment with PI3K inhibitor LY294002 and AKT inhibitor MK-2206 substantially decreased the expression levels of the p-AKT and p-pI3K proteins (p < 0.05) and hence reduced cell survival. Furthermore, Co-Immunoprecipitation (Co-IP) and confocal microscopy experiments revealed a significant interaction between the PI3K/AKT signaling pathway and FKBP10. Conclusions: The present study shows that vemurafenib resistance can be reversed through FKBP10 knockdown
Therapeutic Effect and Mechanism of Emodin on Migraine via Inhibition of TRPV4/p38 Signaling Pathway in a Nitroglycerin-Induced Rat Model
No full textBackground: Migraine is known as a persistent neurological condition marked by recurring bouts of head pain and diverse neurological manifestations. Emodin exhibits a wide range of pharmacological activities, particularly its neuroprotective effects on neurodegenerative diseases. Emodin is capable to alleviate nitroglycerin (NTG)-induced migraine in rats. Furthermore, it has been witnessed that transient receptor potential vanilloid-4 (TRPV4)/p38 signaling pathway is involved in the development of migraine pathogenesis. Methods: Rats subjected to repetitive NTG administration were considered a model replicating clinical manifestations of migraine. Three different Emodin dosage groups (high, medium, and low) and control group were used to observe the effects of different doses on the behavior and other related indicators of migraine rats. Results: The results showed that high and medium doses of Emodin significantly delayed the appearance time of redness and scratching in the ears of rats, shortened their disappearance time, and increased the mechanical pain threshold of rats, indicating that Emodin can remarkably improve the behavior of migraine rats and increase their mechanical pain threshold. At the same time, high and medium doses of Emodin significantly increased the content of peripheral blood 5-hydroxytryptamine (5-HT) in migraine rats, indicating that Emodin can treat migraine headaches by increasing the peripheral blood 5-HT content. In addition, high and medium doses of Emodin can reduce the expression of TRPV4 protein and p38 mRNA in the trigeminal ganglion of migraine rats, indicating that Emodin can negatively regulate the expression and gene transcription of TRPV4/p38 signaling pathway-related proteins. Therefore, it inhibits neuroinflammation, reduces pain-induced sensitization, and exerts a therapeutic effect on migraine. Conclusions: Our findings demonstrate that Emodin is capable to mitigate headaches, which are associated symptoms in migraine-afflicted rats. This effect is likely attributed to the elevation of peripheral blood 5-HT content and the suppression of expression and gene transcription related to the TRPV4/p38 signaling pathway
MitoQ Activates the AMPK-SIRT1 Pathway to Inhibit Pyroptosis in Lung Epithelial Cells and Alleviate Sepsis-Induced Acute Lung Injury
No full textObjective: The mitochondrial coenzyme Q (MitoQ) has protective effects against oxidative stress and inflammatory responses. This study investigated the potential effect of MitoQ on alleviating sepsis-induced acute lung injury (ALI) by activating the adenosine monophosphate-activated protein kinase (AMPK)-sirtuin1 (SIRT1) pathway. Methods: The in vivo sepsis-induced ALI rat model and the in vitro A549 ALI cell model were used in this study. However, the untreated rats or cells were used as the control group and the MitoQ-treated models were used as the experimental group. The hematoxylin and eosin (H&E) staining was used to stain lung tissues. The effects of MitoQ were observed by calculating lung weight and lung permeability index (LPI). Furthermore, the levels of occluding, claudin-1, zonula occludens-1 (ZO-1), tumour necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1), caspase-3, and nuclear factor-kappaB (NF-κB) were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), for evaluating the junction integrity, apoptosis, and inflammation. Moreover, to examine the effect of MitoQ on the AMPK-SIRT pathway, the levels of p-AMPK/AMPK, and SIRT1 were evaluated using Western blot analysis. Additionally, the levels of gasdermin D (GSDMD), cleaved caspase 1, cleaved caspase 11, and lactate dehydrogenase (LDH) were used to investigate the effect of MitoQ on cell pyroptosis and cell damage. Additionally, the role of AMPK and SIRT1 pathways on pyroptosis and cellular damage was determined. Results: In the lung tissues of the ALI model group, the H&E-stained area (p < 0.01), the lung wet/dry weight ratio (p < 0.01), and the LPI were significantly increased (p < 0.01). Moreover, these values were counteracted with MitoQ treatment (p < 0.05). The ALI rats treated with MitoQ survived longer than those without treatment (p < 0.01). Furthermore, in the ALI model group (both in tissues and cells), a significant decrease was observed in the levels of occludin, claudin-1, ZO-1, caspase-3, and NF-κB (p < 0.01), while the levels of TNF-α, IL-1β, MCP-1, cleaved GSDMD, cleaved caspase-1, cleaved caspase-11, and LDH were significantly increased (p < 0.01). Interestingly, treatment with MitoQ reversed all of these factors (p < 0.05). In the ALI model group, the levels of p-AMPK/AMPK and SIRT1 proteins were significantly decreased (p < 0.01), and their levels were reversed following MitoQ treatment (p < 0.05). Furthermore, the compound C (CC) decreased the levels of p-AMPK/AMPK and SIRT1 (p < 0.01), while the SIRT1 antagonist Ex-527 decreased only the level of SIRT1 (p < 0.01). However, both the CC and Ex-527 reversed the levels of cleaved GSDMD (p < 0.01), cleaved caspase-1 (p < 0.05), cleaved caspase-11 (p < 0.01), and LDH (p < 0.01), which were inhibited by MitoQ in ALI cells. Conclusion: Our findings suggest that MitoQ exerts protective effects on sepsis-induced ALI by activating the AMPK-SIRT1 pathway and inhibiting pyroptosis. These results offer a potential therapeutic application of MitoQ in treating sepsis-induced lung injury and provide insights into the underlying mechanisms involved
STAT3 Mediated Inflammation is Involved in Diabetes Mellitus-Related Dry Eye in Rats
No full textBackground: Dry eye is an ocular complication of diabetes mellitus. Due to its complex pathogenesis, treatment still needs to be studied. Objectives: This study aimed to explore the role of signal transducer and activator of transcription 3 (STAT3) in diabetes mellitus-related dry eye. Methods: High-fat and high-carbohydrate diet and streptozotocin were used to establish a diabetes mellitus-related dry eye rat model. All rats were divided into four groups (n = 6 in each group), including control group, diabetes mellitus-related dry eye group (model group), vehicle group, and STAT3 inhibitor group (S3I-201 group). Tear production was assessed using phenol red cotton threads. A CochetBonnet esthesiometer was used to evaluate corneal sensitivity. Periodic acid-schiff (PAS) and in situ terminal deoxynucleotidyl transferase (TUNEL) staining were conducted to measure the number of goblet cells and apoptotic cells in conjunctivae. Enzyme-linked immunosorbent assay (ELISA) was employed to determine the levels of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-17A (IL-17A), and Interleukin-1β (IL-1β) in the conjunctival tissues. Western blot was applied for assessing the expression of nuclear factor-κB (NF-κB)/STAT3 pathway related proteins. Results: S3I-201 increased tear production, corneal sensitivity, the number of goblet cells, and decreased cell apoptosis in diabetes mellitus-related dry eye rats (p < 0.05). Moreover, diabetes mellitus-related dry eye has the potential to induce inflammation by upregulating the levels of TNF-α, IL-6, IL-17A, and IL-1β (p < 0.05), which were significantly reduced after S3I-201 treatment (p < 0.05). In addition, diabetes mellitus-related dry eye induced activation of NF-κB pathway and increased the ratio of p-STAT3/STAT3, both of which were reversed by S3I-201 treatment (p < 0.05). Conclusions: Inhibition of STAT3 alleviated diabetes mellitus-related dry eye in rats by regulating the inflammation
Chemokine and Receptor Family Gene-Based Prognostic Signature for Predicting Clinical Outcomes and Treatment Response in Glioblastoma
No full textBackground: Chemokines and receptor (CCR) genes are closely associated with tumorigenesis and progression. However, their function in the malignant progression of glioblastoma (GBM) is unknown. The present study aims to reveal prognostic factors, molecular subtypes, and prognostic indicators in chemokine genes and receptor genes in GBM. Methods: In this study, expression profiles in The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas (CGGA), and University of Cingifornia Sisha Cruz (UCSC xnea) were utilized for expression analysis of chemokine/receptor genes in pan-cancer and GBM. Univariate COX models identified chemokine/receptor genes with prognostic value. Chemokine/receptor-related gene types in GBM were determined by consistency clustering analysis. This study constructed a prognostic model (CCR Score) using differentially expressed genes (DEGs) between genotypes. Differences between prognosis, tumor mutation burden (TMB), immune checkpoint genes, tumor microenvironment (TME), and drug sensitivity were explored in CCR Score groups and gene types. Results: Expression models of chemokine/receptor genes were explored, and two differentially characterized genotypes (CCR1 and CCR2) were identified in pan-cancer and GBM. CCR1 and CCR2 exhibited different prognoses, TMB, and TME activity. RTK-RAS (56.2%), PI3K (50.4%), TP53 (30.8%), NOTCH (28.8%), and Hippo (25.2%) pathways had a higher percentage of variants. Next, based on the DEGs in CCR1 and CCR2, we constructed a prognostic model (CCR Score) for predicting the prognosis of GBM patients. The CCR Score showed excellent prognostic and predictive performance, and patients with high CCR Score and CCR1 showed better immune activity and were more sensitive to immunotherapy. In addition, the CCR Score was significantly correlated with cancer chemotherapy sensitivity. Conclusion: Overall, we identified the CCR characteristics of GBM patients prognosis, and the CCR Score helps elucidate the potential link between GBM progression and chemokines/receptors and helps explore the mechanisms of carcinogenesis and therapeutic strategies