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Protective Effect of Ketotifen on Cardiac Dysfunction in Septic Rats Induced by LPS through Regulation of the PD-1/PD-L1 Pathway
No full textBackground: Ketotifen is a leukotriene receptor antagonist that exerts anti-inflammatory effects primarily by antagonizing leukotriene B4 receptors. While the effect of ketotifen on sepsis-induced cardiac dysfunction remains to be further explored and its underlying mechanisms remain unclear. Hence, this study aimed to investigate the role and mechanisms of ketotifen in sepsis-induced cardiac dysfunction. Methods: Rats were divided into five groups (n = 5 each group): control group, sepsis group, sepsis + low-dose ketotifen (1 mg/kg) group, sepsis + high-dose ketotifen (10 mg/kg) group and Healthy control group (HC group). Sepsis was induced by intraperitoneal injection of Lipopolysaccharide (LPS) at a dosage of 5 mg/kg and controls received Phosphoric acid buffer solution (PBS) injections instead. Ketotifen was intraperitoneally injected immediately before sepsis induction at doses of 1 or 10 mg/kg. The serum levels of inflammatory cytokines were determined and myocardial tissues were harvested. Results: Compared to sepsis model group, ketotifen administration significantly alleviated sepsis-induced cardiac dysfunction, manifested as reduced serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 17 (IL-17), tumor necrosis factor α (TNF-α), receptor for advanced glycation end products (RAGE) and soluble receptor for advanced glycation end products (sRAGE) (p < 0.05), increased left ventricular fractional (LVFS) (%) and left ventricular ejection fraction (LVEF) (%) detected by echocardiography (p < 0.05), improved myocardial structure shown by electron microscopy and reduced expression of transient receptor potential ankyrin 1 (TRPA1) in myocardial tissues of septic rats (p < 0.05). By western blotting, our results showed that the expressions of programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), V-domain Ig suppressor of T cell activation (VISTA) as well as Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were remarkably elevated in sepsis model group (p < 0.05), and administration of ketotifen significantly downregulate the expressions of them. Conclusion: Ketotifen exerted beneficial effects against cardiac dysfunction induced by sepsis in rats. The cardioprotective effect of ketotifen was possibly attributed to inhibiting PD-1/PD-L1 pathway in myocardial tissues of septic rats
Return to Sports and Physical Activities Following Mobile-Bearing Unicompartmental Knee Replacement
No full textBackground: Physical activity after a joint replacement surgery is one of the most important factors for a satisfactory quality of life for the patients. This study aimed to assess postoperative pain, rate of return to sports, intensity of athletic involvement, postoperative functional outcome, and level of satisfaction after unicompartmental knee replacement (UKR) with a mobile-bearing prosthesis at a minimum follow-up of two years after surgery. Methods: Forty-two patients who had previously undergone a mobile-bearing UKR surgery were enrolled in the study. The mean age at surgery was 67.8 ± 2.5 years. The average follow-up was 3.2 ± 1.5 years. Sports activity was reported for each patient. Visual Analog Scale (VAS), Tegner activity level, Knee Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee Subjective score were determined. Data were analyzed to detect statistically significant differences between preoperatory status and follow-up. Results: The mean KOOS demonstrated a statistically significant difference from preoperative (48.7 ± 5.4) to postoperative (86.5 ± 4.7; p < 0.0001) status. VAS scores significantly decreased from a median of 6.5 (range 2 to 9) to 1.0 (range 0 to 3) at follow-up (p < 0.0001). Tegners activity level increased from a median of 3.5 (range 1 to 6) preoperatively to a median of 4.5 (range 1 to 8) postoperatively (p < 0.0001). Eighty-three percent of patients (35 of 42) returned to sports activities successfully. In the subgroup of patients engaged in a sport before surgery, the percentage increased to 92%. Conclusions: Evidence suggests that mobile-bearing UKR enables a significant percentage of patients suffering from unicompartmental knee osteoarthritis to resume sports activity while also improving pain scores and overall functional and subjective outcomes. Most patients who successfully returned to physical activity engaged in low-impact sports
Regadenoson Inhibits the Formation of Neutrophil Extracellular Traps, Alleviating Endothelial Injury Caused by Decompression Sickness
No full textBackground: Decompression sickness (DCS) is a common condition found in divers. However, the role of neutrophil extracellular traps (NETs) in the development of DCS is still unknown. This study sought to investigate the underlying mechanism of endothelial injury caused by NETs. Methods: A DCS mouse model was developed to assess the therapeutic effect of regadenoson (a selective A2A adenosine receptor agonist) in these models. The mice were divided into three groups: the control, model, and model+regadenoson (REG) groups. The DCS mouse model was established by applying a computer-controlled steel hyperbaric oxygen chamber to create a DCS-like environment. Moreover, the histopathological score of the lung tissues excised from treated mice was determined using Hematoxylin and Eosin (H&E) staining. Furthermore, the levels of tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10), IL-16, IL-13, and IL-1β were evaluated using Real-time PCR. NETs were assessed using the double fluorescence staining method. Additionally, the activation levels of the phosphatidylinositol-3 kinase/a serine/threonine protein kinase (PI3K/AKT) signaling pathway were determined using Western blot analysis. Results: We found that regadenoson contributed to reducing lung inflammation and vascular endothelial injury. Additionally, regadenoson activated A2A receptors and upregulated the expression of prefoldin subunit 6 (PFDN6) protein (p < 0.05), thereby suppressing the formation of NETs. Moreover, NETs adversely affected the viability, and migration ability and caused cellular injury of endothelial cells by inhibiting a serine/threonine protein kinase (AKT) signaling pathway. However, regadenoson interrupted this effect by suppressing the formation of NETs. Moreover, regadenoson significantly reduced lung inflammation and endothelial damage (p < 0.05). Conclusions: Regadenoson holds promising potential in treating DCS
Antifungal Activity of Functionalized Hyperbranched Polyethyleneimine Derivatives against Quiescent Conidia and Germlings of the Opportunistic Fungal Pathogen Aspergillus nidulans
No full textBackground: Drug resistance is the major problem for all of the currently available antifungals and, therefore, a completely novel class of antifungal compounds is an urgent need. The aim of this study is to investigate whether appropriately functionalized cationic dendritic polymers that have extensively been studied as drug delivery systems and/or antibacterial agents exhibit fungicidal activity and thus could be used as antifungals. Methods: In this work, hyperbranched polyethyleneimine and its end-group functionalized guanidinylated or quaternized derivatives were synthesized and their antifungal activity was evaluated against the opportunistic pathogen Aspergillus nidulans (A. nidulans) as a model eukaryotic microorganism. Specifically, their subcellular localization in germlings originating from fungal conidiospores, their effect on fungal growth and their ability to cause cell death in both hyphae and quiescent conidia, were studied using confocal laser and epifluorescent microscopy, the colony forming unit (CFU) assay and the propidium iodide (PI) staining assay. Results: It was found that polyethyleneimine (PEI) was the most effective compound causing complete growth inhibition at relatively lower minimum inhibitory concentration (MIC) of ca. 2 μg/mL compared to the guanidinylated (GPEI) (3 μg/mL) or quaternized (QPEI) (5 μg/mL) derivatives. More importantly, the compounds prevent quiescent conidiospore germination and, therefore, the formation of hyphae and mycelium. Employing the fluorescently-labeled derivatives, it was evident that the compounds are initially localized in the plasma membrane of both quiescent conidiospores and hyphae, while subsequently enter the cytoplasm, without showing localization in specific subcellular organelles. Appropriate staining with propidium iodide (PI) revealed that the membrane of cells, grown in the presence of all tested polymers at concentrations above the minimum inhibitory concentration (MIC), exhibits increased permeability to the dye, suggesting that the primary cause of cell death is the disruption of the plasma membranes integrity. Furthermore, by employing the CFU assay it was evident that a significant percentage of fungal conidiospores exhibited inability to recover growth following treatment with the examined compounds and that their survival was reduced by up to 70% (p < 0.001). Conclusions: Our results showed that the cationic hyperbranched polymeric compounds PEI and its derivatives GPEI and QPEI exhibited apparent fungicidal activity on A. nidulans cells. In addition, all compounds showed negligible in vitro cytotoxicity against three mammalian cell lines in this concentration range. Overall, our results suggest that the investigated polymeric compounds are promising antifungals and their activity deserves further investigation especially against drug-resistant fungal cells
Unravelling the Interplay between Biomolecular Condensates and RNA in Cancer and Diseases
No full textBiomolecular condensates (BCs), including membraneless organelles, are basically Ribonucleic acid (RNA)-protein complexes that are emerging as a potential candidate because of its paramount significance in revealing fundamentals of cell biology and pathology including cancer. Aiming to understand its importance, scientists are dealing with it in an interdisciplinary manner—from polymer chemistry to genetics. Over time the mechanism of liquid-liquid phase separation (LLPS) and the model of ‘Stickers and Spacers’ have widened our understanding and broadened our scope of approaches to get insights into these molecular entities. RNA molecules and its specific partner proteins, certain ribonucleoproteins (RNPs), play pivotal roles in different trajectories of BCs, i.e., in localization, compartmentalization, epigenetic regulation, and dynamics. However, several aspects need to be made clearer to tackle human diseases including cancer. In addition to the RNAs, in this review specific aspects of the BCs are presented in the context of neurodegenerative diseases, viral infections and cancer, and their link with stress granules (SG), P bodies, paraspeckles, and host encoded and viral encoded non-coding RNAs, discussing cancer associated proteins, tumour suppressors and repressors, dysregulation of cancer signals, and role of super enhancers. A special focus is reserved to oncolytic viruses and epidemic viruses, through the intervention on stress granule protein partners, virus-formed intracellular condensates, and viral RNAs. The review covers not only the basics of BCs but also encompasses the emerging context of condensate-targeted drug discovery and cancer therapeutics by means of Proteolysis-targeting chimera (PROTAC), Ribonuclease-targeting chimera (RIBOTAC), small molecule inhibitors of protein-RNA interactions, Antisense oligonucleotides (ASO) and compounds targeting non-coding RNA (ncRNA) triple helix, determining RNA degradation
Correlation of Serum Levels of Inflammatory Chemokines (CXCL13, MCP-1, CCL11) with Severity and Prognosis of Acute Cerebral Infarction Patients
No full textBackgrounds: Acute cerebral infarction significantly impacts the quality of life and prognostic outcomes for affected individuals. Inflammation is crucial in the pathological and physiological processes following acute cerebral infarction. Investigating the correlation of CXC chemokine ligand 13 (CXCL13), monocyte chemoattractant protein-1 (MCP-1), and CC chemokine ligand 11 (CCL11) with the severity and prognosis of acute cerebral infarction patients may contribute to the identification of new biomarkers and pathophysiological mechanism, thereby enhancing treatment and rehabilitation. Methods: We enrolled 150 patients with acute cerebral infarction and 100 healthy controls. Patients were categorized into mild (National Institutes of Health Stroke Scale (NIHSS) score <7), moderate (7≤ NIHSS score <15), and severe (NIHSS score ≥15) subgroups based on their NIHSS scores. According to the modified Rankin scale (mRS) score, patients were further divided into good prognosis (mRS score ≤2) and poor prognosis (mRS score >2) subgroups. Serum concentrations of CXCL13, MCP-1, and CCL11 were compared. Multivariate logistic regression was used to analyze risk factors for moderate and severe neurological impairment and poor prognosis in acute cerebral infarction patients. Spearman rank correlation analysis was used to explore the correlation of CXCL13, MCP-1, and CCL11 with NIHSS and mRS scores. Results: In the study group, concentrations of CXCL13, MCP-1, and CCL11 were significantly higher, with the severe subgroup > moderate subgroup > mild subgroup and poor prognosis subgroup > good prognosis subgroup, compared to the control group (p < 0.05). Elevated concentrations of CXCL13, MCP-1, and CCL11 emerged as independent risk factors for moderate and severe neurological impairment and poor prognosis in acute cerebral infarction patients (p < 0.05). Serum CXCL13, MCP-1, and CCL11 demonstrated positive correlations with NIHSS and mRS scores in acute cerebral infarction patients (p < 0.05). Conclusion: CXCL13, MCP-1, and CCL11 likely play a role in the onset and progression of acute cerebral infarction. Their concentrations positively correlate with NIHSS and mRS scores, providing insights into the degree of neurological impairment and prognosis in affected patients
Study of Epicardial Fat Lipid in Coronary Heart Disease on the Regulation Mechanism of Metabolism
No full textObjective: Coronary heart disease (CHD), emerging as a common chronic disease, is threatening the lives of middle-aged and older people in China, with a gradual increase in morbidity and mortality. However, the metabolic mechanism of CHD remains unclear, necessitating a comprehensive elucidation. Therefore, this study aimed to examine the underlying regulatory mechanism of epicardial lipid metabolism in CHD. Methods: This study collected epicardial adipose tissue samples (n = 40), including 20 patients with CHD and 20 non-CHD. 3T3L1 was induced to differentiate into mature adipocytes in vitro and subsequently treated with different concentrations of oxidized low-density lipoprotein (ox-LDL), glucose, and lipopolysaccharide (LPS). The contents of glycerol and triglyceride were determined using corresponding kits. Moreover, the concentrations of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) were assessed utilizing ELISA. Furthermore, western blotting analysis and qRT-PCR were employed to determine protein and mRNA expression levels. Additionally, immunofluorescence analysis was utilized to assess the expression of lipid droplet coating protein perilipin A. The morphology and count of lipid droplets were observed using a confocal microscope. Results: Compared to the non-CHD group, the level of triglyceride and perilipin A increased significantly, while the content of glycerol, PKA, cAMP, adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) decreased in the CHD group. Furthermore, high ox-LDL and glucose significantly decreased small lipid droplets, glycerol, ATGL, and HSL while substantially increasing large lipid droplets, triglyceride, cAMP, PKA, and perilipin A in 3T3L1 cells. Additionally, high LPS concentration significantly increased small lipid droplets, glycerol, cAMP, PKA, ATGL, and HSL, and decreased large lipid droplets, triglyceride, and perilipin A. Conclusions: In summary, high ox-LDL and glucose levels regulate the lipolysis of 3T3L1 adipocytes by regulating the cAMP-PKA and perilipin A-ATGL-HSL pathways. However, high LPS can promote the hydrolysis of 3T3L1 adipocytes
Mitochondrial Transplantation Inhibited the Growth of Cholangiocarcinoma Cells by Inhibiting the Aerobic Glycolysis Pathway
No full textBackground: Cholangiocarcinoma (CCA) is a type of cancer that originates from the biliary system. It typically has a subtle onset and high degree of malignancy, often leading to a terminal stage diagnosis, which limits the possibility of surgical intervention. Recent advancements in mitochondrial transfer therapy have enabled more precise treatment of CCA. This study aimed to investigate the effects and potential mechanisms of normal mitochondrial transplantation on the proliferation and energy metabolism of cholangiocarcinoma cells. Methods: The human cholangiocarcinoma cell line HuCCT1 was randomly divided into 5 groups: control (Con) group, mitochondrial transplantation 1 h (Mito-1 h) group, mitochondrial transplantation 6 h (Mito-6 h) group, mitochondrial transplantation 12 h (Mito-12 h) group, and mitochondrial transplantation 24 h (Mito-24 h) group. HuCCT1 cells received 143B wild-type mitochondrial fusion cells (143BρW)-derived mitochondria for different periods. Cell proliferation was detected using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was assessed using immunofluorescence and flow cytometry. Glycolytic activity was measured using commercial kits. RNA-seq was employed to analyze the differentially expressed genes (DEGs) in HuCCT1 cells following mitochondrial transplantation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed for further interpretation of the data. Protein expression levels were evaluated using western blot. Results: Normal mitochondria were successfully extracted from 143Bρw. Mitochondrial transplantation inhibited proliferation and promoted apoptosis of HuCCT1 cells. Western blot analysis suggested that mitochondrial transplantation significantly enhanced the expression of the mitochondrial apoptosis pathway, including Cytochrome C (Cyto-C), apoptosis-inducing factor (AIF), phosphorylated p53 (p-p53) and cleaved-Caspase-9. Moreover, mitochondrial transplantation enhanced the glucose uptake of HuCCT1 cells. Meanwhile, the levels of lactate acid, adenosine triphosphate (ATP), and Nicotinamide adenine dinucleotide phosphate (NADPH) were decreased by mitochondrial transplantation. Finally, RNA-seq results show that mitochondrial transplantation resulted in 60 significantly differentially expressed genes in HuCCT1 cells. Bioinformatics analysis indicated that the pentose phosphate pathway, Notch signaling pathway, Voltage-gated potassium channel complex, and insulin signaling are potential pathways for mitochondrial transplantation to inhibit CCA progression. Conclusions: Mitochondrial transplantation has the potential to impede cholangiocarcinoma cell proliferation by modulating energy metabolism, thus presenting a promising therapeutic strategy for this malignancy
Inhibition of DDX60 Expression Suppresses Oral Squamous Cell Carcinoma Growth and Enhances Radiosensitivity
No full textPurpose: DEXD/H box helicase 60 (DDX60) overexpression in oral squamous cell carcinoma (OSCC) specimens has been reported extensively. Nevertheless, the radiosensitization implications of high-level DDX60 expression in OSCC remain unknown. This study aimed to investigate the biological function of DDX60 and confirm whether the inhibition of DDX60 could enhance radiosensitivity. Methods: DDX60 expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis. After combination treatment of irradiation with or without DDX60-siRNA (small interfering RNA), the cell malignant behavior was determined using cell counting kit-8 (CCK-8) assay, flow cytometry, and transwell assays. The HSC6 xenograft models were utilized to measure the in vivo effects of combined treatment. Results: DDX60 was overexpressed in OSCC tissues and cells (p < 0.01, p < 0.05). HSC6 and SAS cells were transformed with DDX60-siRNA plasmids specifically reduced DDX60 gene expressions (p < 0.001, p < 0.01). DDX60 silencing notably hindered the proliferation and invasive abilities, and accelerated the apoptosis process (p < 0.01, p < 0.05). Suppression of DDX60 could enhance the 4 Gy irradiation-induced inhibiting in OSCC cell proliferation and invasion in HSC6 and SAS cells (p < 0.01, p < 0.05). Furthermore, the inhibition of DDX60 could promote the 4 Gy irradiation-induced apoptosis in HSC6 and SAS cells (p < 0.01, p < 0.05). Suppression of DDX60 also inhibited tumor growth in the HSC6 xenograft model (p < 0.01). Conclusions: The inhibition of DDX60 expression can promote radiosensitizing activity in human OSCC. Our results reveal that a multimodal therapy involving DDX60 expression inhibitors might be an effective radiosensitizer strategy in OSCC
18F-FDG Positron Emission Tomography in Myocardial Viability Assessment: Oral Glucose and Intravenous Insulin Loading Protocol vs Fasting Status Protocol
No full textBackground: Determination of myocardial viability is vital for coronary revascularization in patients with ischemic cardiomyopathy (ICM). To select the appropriate strategies for ICM screening, the present study compared the image quality, viability extent, and dyssynchrony of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) myocardial viability imaging in patients with ICM using an oral glucose and intravenous insulin loading (G/I) protocol with a convenient fasting status (FAST). Methods: 18F-FDG PET metabolic imaging was conducted using the G/I and FAST protocols on different days and 99mTc-methoxyisobutylisonitrile (MIBI) perfusion imaging in all patients (N = 44). Fluorodeoxyglucose (FDG) image quality was assessed using a 5-point scoring system. The semiquantitative analysis included SUVmean of blood pool (SUVmeanBlood), SUVmax of the whole left ventricular muscle (SUVmaxMyo), and the SUVmeanBlood and SUVmaxMyo ratio (M/B). Furthermore, the quantitative analysis involved comparing the extent of mismatch on polar maps and evaluating left ventricle dyssynchrony between the two groups. The Cohen κ-test was used to investigate positive or negative on left anterior descending (LAD), left circumflex (LCX) or right coronary artery (RCA) between the groups. Results: The imaging quality scores were 4.36 ± 0.94 and 3.55 ± 1.09 using the G/I and FAST protocols, respectively (p < 0.001). Significant differences were found in SUVmeanBlood, SUVmaxMyo, and M/B between the two groups (p < 0.001, 0.007, and <0.001, respectively). G/I and FAST protocols indicated good agreement for positive and negative findings in the LAD, LCX, and RCA (κ = 0.847, 0.858, and 0.74, respectively). Myocardial viability assessment exhibited equivalence between the two groups (all p > 0.05) within the imaging score ranging from 3 to 5. Furthermore, dyssynchrony assessment of left ventricle exhibited no significant difference between the two groups (all p > 0.05). For the G/I method, insulin consumption (95% confidence interval (CI) 0.03–0.27, p = 0.014) and SUVmaxMyo (95% CI 0.07–0.24, p = 0.0005) were identified as significant predictors for metabolic imaging score (coefficient of determination (R2) = 0.6226). Similarly, for the FAST protocol, SUVmaxMyo (95% CI 0.09–0.29, p = 0.0003) was a significant predictor for metabolic imaging score (coefficient of determination (R2) = 0.6787). Conclusions: Our findings indicate that 18F-FDG PET in assessing myocardial viability using the FAST protocol could be a time-efficient and safe option for clinical personalized practice. Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR2400083975)