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Biological Information Analysis on the Correlation between Sepsis and Cognitive Dysfunction
No full textBackground: Sepsis and mild cognitive impairment (MCI) are two distinct clinical conditions that often interact in their progression. However, the potential shared pathological mechanisms of these two diseases are yet to be explored. This study aims to investigate differentially expressed genes (DEGs) in sepsis and cognitive dysfunction using biological data methods. The goal is to delve into their shared genetic characteristics and underlying molecular mechanisms, providing innovative ideas for the treatment of sepsis in combination with MCI. Methods: Gene expression profiles for sepsis (GSE131761) and cognitive dysfunction (GSE63060) were accessed from the gene expression omnibus (GEO) database. The data were analyzed using R software (version 4.3.2, R Core Team, Vienna, Austria) to identify DEGs between sepsis and MCI. Furthermore, annotation of the biological pathways was performed using the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. Additionally, the STRING database and Cytoscape software were employed to construct a protein-protein interaction (PPI) network and screen the key genes. Finally, the hub genes were validated using external datasets (GSE46955, GSE63061, GSE137342). Results: It was found that 36 DEGs were shared between sepsis and MCI. Furthermore, biological processes were significantly enriched within key pathways such as cellular respiration, oxidative phosphorylation, aerobic respiration, and ATP synthesis coupled electron transport. In terms of cellular components, these DEGs were enriched in the inner mitochondrial membrane protein complex, respiratory chain complex, mitochondrial respirasome, and mitochondrial protein-containing complex. Regarding molecular function, they were enriched in structural constituent of ribosome, Nicotinamide adenine dinucleotide (NADH) dehydrogenase activity, and oxidoreductase activity. Furthermore, the KEGG analysis enriched these genes in Parkinsons disease, oxidative phosphorylation, thermogenesis, neurodegeneration, and prion disease. The PPI network analysis revealed 10 hub genes, including cytochrome c oxidase subunit 7C (COX7C), NADH:ubiquinone oxidoreductase subunit B3 (NDUFB3), ubiquinol-cytochrome c reductase complex III subunit VII (UQCRQ), cytochrome c oxidase subunit 7A2 (COX7A2), NDUFA4 mitochondrial complex associated (NDUFA4), ATP synthase peripheral stalk subunit F6 (ATP5PF), NADH:ubiquinone oxidoreductase subunit A1 (NDUFA1), SRA stem-loop interacting RNA binding protein (SLIRP), cytochrome c oxidase copper chaperone COX17 (COX17) and small nuclear ribonucleoprotein polypeptide G (SNRPG). The validation results with external datasets showed that reduced efficiency of oxidative phosphorylation was a common mechanism of sepsis and MCI. Conclusion: This study identified pathological mechanisms between sepsis and MCI. Moreover, this study identified key genes and their regulatory pathways, and their core mechanisms might be linked to oxidative phosphorylation, providing a theoretical basis for understanding their genetic linkage, and offering innovative ideas for future research
Evaluation of the Effects of Pistacia atlantica Desf. Oleo-Gum-Resin and Its Nanocapsulated Form on Biomechanical Properties and Bone Density in a Rat Model of Ovariectomy-Induced Osteoporosis
No full textBackground: Pistacia atlantica Desf. oleo-gum-resin as a herbal medicine has been claimed to be effective for treating bone disorders in traditional Persian medicine and has been used by traditional practitioners and regional healers, especially in the west of Iran, to manage osteoporosis and fractures for a long time. Since no study has been performed on the effects of P. atlantica (Pistacia atlantica) oleo-gum-resin on bone and bone-related disorders, the present study aimed to investigate the therapeutic effects of standardized resin in the ovariectomy-induced osteoporosis rat model. Materials and Methods: The essential oil of P. atlantica oleo-gum-resin was analyzed by gas chromatography. Osteoporosis was induced in rats by ovariectomy. For eight weeks, three doses of gum and its encapsulated form (50, 100 and 200 mg/kg) were given through gavage to ovariectomized rats. The body weight, serum biochemical parameters including Calcium (Ca) and serum alkaline phosphatase (ALP), Hounsfield Unit (HU) of bone, and bone biomechanical properties were measured and compared with positive control (0.1 mg/kg/day alendronate). Results: Alpha-pinene was detected as the main constituent of oleo-gum-resin with a concentration of 127.479 mg/mL. All three doses of gum and its encapsulated form significantly improved serum calcium and biomechanical properties of bone and decreased alkaline phosphatase compared to the control group (p < 0.05). Only encapsulated form at 200 mg/kg doses resulted in Hounsfields improvement. The nanocapsulated form showed better results on the investigated parameters than the fresh gum. Conclusions: P. atlantica demonstrated osteoprotective effects, probably due to the high content of Alpha-pinene. Clinical trials are required to confirm its effectiveness in managing postmenopausal osteoporosis
Identification of Immune Infiltration Consensus Genes and Their Clinical Value in Early and Advanced Non-Small Cell Lung Carcinoma
Full text linkBackground: Lung cancer stands as the leading cause of cancer-related mortality globally, with non-small cell lung carcinoma (NSCLC) accounting for approximately 85% of all lung cancer cases. Despite advancements in diagnostic techniques and therapeutic interventions, the 5-year survival rate for NSCLC remains low due to the recurrence and dissemination of malignant cells. There is an urgent need to identify novel biomarkers and therapeutic targets to address this challenge. Therefore, this study aims to identify common genes associated with tumor-related immune cells and investigate their potential clinical utility in both early and advanced NSCLC. Methods: Early-stage and advanced NSCLC expression data, mutation data, and associated medical records were obtained and refined for subsequent examination from The Cancer Genome Atlas (TCGA). Differential expression analysis, gene ontology (GO), transcription factors and pathway enrichment analysis, and gene set enrichment analysis (GSEA) were implemented to discern molecular function and regulatory relationship across differentially expressed genes (DEGs). Single-sample gene set enrichment analysis (ssGSEA) was employed to analyze immune cell abundance. Furthermore, the weighted gene co-expression network analysis (WGCNA) of DEGs was utilized to screen out gene modules related to tumor-associated immune cells in early-stage and advanced NSCLC. This was achieved by the tumor immune estimation resource (TIMER) algorithm to assess immune cell abundance. Subsequently, consensus genes associated with drug sensitivity and pathways activity were analyzed using the Gene Set Cancer Analysis Literate (GSCALite) platform. Notably, we also evaluated the correlation between consensus genes expression and TP53 mutant (TP53mut) and TP53 wild-type (TP53wt). Finally, the KMPlotter online tool was used to evaluate the prognostic implications of consensus genes exhibiting different correlation patterns in NSCLC. Results: In early and advanced NSCLC, there were 996 (445 upregulations and 551 downregulations) and 822 (398 upregulations and 424 downregulations) DEGs from lung adenocarcinoma (LUAD) versus lung squamous cell carcinoma (LUSC), respectively, following differential expression analysis. In the interferon signal pathway, functional enrichment analysis showed significant enrichment of DEGs. A correlation between immune infiltration and NSCLC was found using ssGSEA. WGCNA analysis revealed a strong association between tumor-immune infiltration characteristics and the blue and turquoise modules. Notably, a total of 27 consensus genes linked to tumor-related immune cells were identified in both early and advanced NSCLC. Furthermore, differential expression patterns were observed for these consensus genes, such as melanoma-associated antigen A 4 (MAGEA4) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1), between TP53 mutant (TP53mut) and TP53 wild-type (TP53wt). Conclusions: This study revealed the crucial role of immune cell infiltration, especially dendritic cells, in the onset and progression of early and advanced NSCLC, providing potential targets for immune therapy
Effects of Immunomodulatory Drugs on Cardiac and Immune Function in Patients with Heart Failure: A Meta-Analysis of Randomized Controlled Trials
No full textBackground: Immune dysfunction exacerbates the progression of heart failure, prompting the use of immunomodulatory drugs to regulate both immune and cardiac function of patients with heart failure. However, the existing therapeutic results are controversial. Therefore, this study aims to systematically evaluate the influence of immunomodulatory drugs on immune and cardiac function in patients with heart failure. Methods: A computerized search was performed on randomized controlled trials (RCTs) related to immunotherapy drugs in patients with heart failure published in Wanfang, China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and other databases from inception to November 2023. Quality assessment was performed using the Cochrane Manual of Systematic Review 5.3, and meta-analysis and sensitivity analysis were carried out using Stata 15.0. Results: 11 studies were included in this meta-analysis. Among patients with heart failure treated with immunomodulatory drugs, left ventricular end-diastolic dimension (LVEDD) [standardized mean difference (SMD) = –0.35, 95% confidence interval (CI): –0.66~–0.04], left ventricular end-systolic diameter (LVESD) [SMD = –0.27, 95% CI: –0.45~–0.10], high sensitivity C reactive protein (hsCRP) [SMD = –1.38, 95% CI: –2.09~–0.67], brain natriuretic peptide (BNP) [SMD = –0.43, 95% CI: –0.72~–0.15], tumor necrosis factor-α (TNF-α) [SMD = –0.73, 95% CI: –1.12~–0.33], interleukin-6 (IL-6) [SMD = –0.71, 95% CI: –0.87~–0.55) ], interleukin-1β (IL-1β) [SMD = –0.58, 95% CI: –0.78~–0.37] and quality of life scores (SMD = –0.32, 95% CI: –0.61~–0.0.04) were significantly inferior compared to the control group. Conversely, left ventricular ejection fraction (LVEF) [SMD = 0.62, 95% CI: 0.20~1.05] and 6-minute walking distance (6MWD) [SMD = 0.89, 95% CI: 0.58~1.21] were higher than the control group; There was no significant difference in interleukin-10 (IL-10) [SMD = 0.31, 95% CI: –0.26~0.88] or adverse events (OR = 1.15, 95% CI: 0.64~2.05) between the two groups. Conclusion: Immunomodulatory drugs can safely improve cardiac function, motor function, immune function, and quality of life in patients with heart failure
Enhancing Bone Fracture Healing via Modulation of the Wnt/ERK Signaling Pathway and Mitochondrial Dynamics with Loxoprofen
No full textBackground: Periosteal stem cells (PSCs) are pivotal in bone tissue repair and regeneration. This study explores the effect of Loxoprofen (Lox) on PSCs’ osteogenic differentiation, focusing on the Wingless/Integrated/Extracellular Signal-Regulated Kinase (Wnt/ERK) signaling pathway and mitochondrial dynamics. Methods: Initially, we induced osteogenic differentiation in PSCs and exposed them to varying concentrations of Lox (5 μg/mL, 10 μg/mL, 20 μg/mL). Employing a murine fracture healing model and Hematoxylin and Eosin (H&E) staining, we assessed Loxs in vivo impact on fracture healing in mice. PSCs proliferation, adhesion, and migration effects under Lox influence were scrutinized using Cell Counting Kit-8 (CCK-8), cell adhesion experiments, and Transwell assays. Furthermore, Loxs effects on Alkaline Phosphatase (ALP) activity, mineralized nodules, osteogenic markers, and Wnt/ERK pathway-associated proteins during PSCs osteogenic differentiation were analyzed via Enzyme-Linked Immunosorbent Assay (ELISA), ALP staining, Alizarin Red staining, western blot, and Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Microscopy was utilized to explore Loxs impact on mitochondrial morphology and cytoskeleton in PSCs post-osteogenic differentiation. Additionally, we measured Loxs effects on adenosine triphosphate (ATP) levels, reactive oxygen species (ROS) levels, and mitochondrial membrane potential in PSCs after osteogenic differentiation with ELISA and flow cytometry. Finally, we demonstrated the inhibitory effect of Wnt/ERK pathway inhibitors (Dickkopf-1 (DKK1)/SCH772984) on Lox-induced Wnt/ERK signaling pathway activation using western blot. Results: Our findings confirm that Lox, at low, medium, and high doses, increases the proliferation, adhesion, and migration capacities of PSCs (p < 0.05). Lox demonstrates a pronounced elevation in the osteogenic potential of PSCs while significantly promoting mitochondrial activity, fusion, and progress of fracture healing (p < 0.05). Additionally, Lox treatment leads to significant enhancement in the activation of the Wnt/ERK signaling pathway (p < 0.05). The addition of Wnt/ERK pathway inhibitors significantly suppressed the effect of Lox on the Wnt/ERK signaling pathway (p < 0.05). Conclusions: Lox facilitates PSCs’ osteogenic differentiation by enhancing the Wnt and ERK signaling pathways and mitochondrial dynamics, contributing to improved fracture healing
Evaluation of Antioxidant and Anti-Inflammatory Activity of Acorus calamus Essential Oil Using in Silico and in Vitro Methods
No full textBackground: Acorus calamus is a perennial herbaceous plant indigenous to wetlands in Asia and Europe. It is also known by the common names Sweet Flag and Calamus. Traditional medicine and perfumery have long utilized its unusual sword-shaped leaves and scented rhizomes. In addition to being treasured for its possible therapeutic benefits, it is a cultural emblem in many communities. The current study investigates the composition of phytoconstituents of Acorus calamus essential oil (ACEO), assesses its drug-likeness properties, performs molecular docking studies with interleukin (IL)-1β, and evaluates its antioxidant and anti-inflammatory activities. Methods: Gas Chromatography-Mass Spectrometry (GC-MS) was used for the analysis of phytoconstituents present in the ACEO. In silico studies were carried out to determine the pharmacokinetics, toxicity, drug-likeliness and interaction of ACEO phytoconstituents with IL-1β. In vitro assays, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and protein denaturation inhibition, were done to investigate the potential antioxidant and anti-inflammatory activities of the bioactive molecules present in ACEO, respectively. Results: GC-MS analysis revealed the presence of 20 secondary metabolites with (Z)-Asarone as the major component (91.44%). In silico analysis showed the drug-likeness of (Z)-Asarone, isoshyobunone, and γ-Asarone. Molecular docking revealed strong binding affinities of these compounds with IL-1β. In vitro experiments demonstrated ACEOs significant (p < 0.01) antioxidant activity at the concentrations 6 and 12 μg/mL with an IC50 value of 6.68 μg/mL, comparable to the standard (ascorbic acid, IC50 = 3.69 μg/mL). ACEO also exhibited significant (p < 0.05) protein denaturation inhibition compared to diclofenac sodium (IC50 = 365.43 μg/mL vs. 446.20 μg/mL). Conclusion: Acorus calamus essential oil primarily composed of (Z)-Asarone, possesses potential antioxidant and anti-inflammatory properties. These findings suggest its therapeutic potential in addressing oxidative stress-related conditions and inflammation-associated diseases, warranting further investigation and development as a natural remedy
N-Acetylcysteine Alleviates Cerebral Ischemia-Reperfusion Injury by Inhibiting the JNK/Caspase-3 Signaling Pathway
Full text linkBackground: Cerebral ischemia-reperfusion injury (CIRI) is a common neurological disorder involving pathways such as cell apoptosis and inflammation. N-acetylcysteine (NAC), an antioxidant and anti-inflammatory agent, is widely studied for various diseases. However, its specific mechanism in CIRI remains unclear. Therefore, this study aims to explore the mechanism of action of NAC in CIRI. Methods: In this study, we utilized a Middle Cerebral Artery Occlusion (MCAO) mouse model to investigate the effects of N-acetylcysteine (NAC) on cerebral ischemia-reperfusion injury (CIRI). The experimental mice were divided into two groups: the Model group and the NAC treatment group. The NAC was administered after the induction of MCAO. The therapeutic outcomes were assessed through behavioral tests and neuropathological examinations. Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was used to measure the levels of inflammatory factors, specifically tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Western blot analysis was employed to assess the expression of apolipoprotein E (APOE) following CIRI. The infarct volume post-CIRI was determined using pathological sections and image analysis. Additionally, the impact of NAC on the c-Jun N-terminal Kinase/Cysteine-aspartic Acid Protease-3 (JNK/Caspase-3) signaling pathway in neuronal cells was examined through immunofluorescence and western blot analysis. Results: NAC treatment improved motor and cognitive functions (p < 0.05), reduced neuronal damage, and increased survival rates (p < 0.05). NAC treatment also led to a decrease in inflammatory factors, including TNF-α, IL-1β, and IL-6 after MCAO (p < 0.01). Furthermore, NAC significantly decreased the expression of APOE (p < 0.01), which contributed to neuroprotection. The administration of NAC also reduced the infarct volume induced by MCAO (p < 0.01) and inhibited cell apoptosis (p < 0.05). Hematoxylin and eosin (HE) staining demonstrated that NAC treatment resulted in reduced structural damage in the hippocampal CA1 region. Immunofluorescence and western blot analyses showed that NAC suppressed the expression of JNK, p-c-Jun, Caspase-3, and Caspase-9 in the oxygen-glucose deprivation (OGD) neuronal cell model (p < 0.01). Conclusions: The findings of this study suggest that NAC alleviates CIRI by inhibiting the JNK and Caspase-3 signaling pathways. This reveals the potential mechanism of NAC in the treatment of CIRI and provides a theoretical basis for its clinical application
Concentrated Growth Factor Enhances the Effect of Hypoxia-Pretreated Adipose-Derived Stem Cell Sheets on Skin Wound Healing
No full textBackground: Most significant wounds often exhibit poor healing. Hence, the exploration of novel approaches to enhance skin wound healing (SWH) and further investigate potential underlying mechanisms remains crucial. Our aim was to delineate the collective impact of concentrated growth factor (CGF) and hypoxia-pretreated adipose-derived stem cell (ADSC) sheets on SWH and investigate the underlying mechanism. Methods: The optimal concentration of CoCl2, a hypoxia-inducing reagent, and CGF extract for cell proliferation and ADSC growth factor production in rats was determined using dose gradient experiments. Mice were categorized into six groups according to ADSC treatment: (A) control, (B) ADSC sheets, (C) ADSC sheets treated with CoCl2, (D) CGF particles, (E) CGF and ADSC sheets, and (F) CGF and ADSC sheet combination treated with CoCl2. The impact of CGF and hypoxia on ADSC proliferation was investigated through western blotting and Cell Counting Kit-8 (CCK-8) assay. Immunohistochemistry, Masson staining, and hematoxylin and eosin staining were conducted ten days after the surgical procedure to assess the effects. Key markers for skin wound healing were evaluated, and the underlying mechanism in human ADSCs was examined. Results: In vitro studies demonstrated synergistic promotion of proliferation, transwell migration, and growth factor production through the combined application of 10% CGF extract and 50 μM CoCl2. This combination notably activated the Integrin-linked kinase (ILK)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1-alpha (HIF-1α) pathway in ADSCs derived from both rats and humans, leading to a significant acceleration of skin wound healing (SWH) in vivo. Conclusion: The acceleration of skin wound healing (SWH) in nude mice was observed when using rat-derived ADSC sheets treated with the combination of CGF and CoCl2, which was achieved through the activation of the ILK/AKT/mTOR/HIF-1α signaling pathway
The Correlations between Complete Blood Cell Count-Derived Inflammatory Indices and Obesity and Mortality Rates: The National Health and Nutrition Examination Survey, 1999–2018
No full textBackground: Inflammation plays a crucial role in the pathogenesis of obesity, and complete blood cell count (CBC)-derived inflammatory indices have increasingly been studied as a novel biomarker class. The relevance of these biomarkers to obesity and prognostic outcomes, however, remains uncertain. Therefore, the present study was designed to assess the associations among CBC-derived inflammatory biomarkers, obesity, cardiovascular disease (CVD) mortality, and all-cause mortality in the general public. Methods: The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to conduct this analysis with data collected from 1999–2018. The relationships between CBC-derived inflammatory biomarkers and obesity were analyzed by multivariate logistic regression. Furthermore, the correlations between these CBC-derived inflammatory biomarkers and both CVD and all-cause mortality in obese individuals were assessed employing a weighted regression approach. However, the linearity of these relationships was evaluated utilizing a restricted cubic spline (RCS) regression approach. Moreover, a random survival forest (RSF) model was used to estimate the relative significance of certain inflammatory biomarkers as risk factors associated with all-cause mortality in obese individuals. Results: Multivariate analyses showed that the highest quartile of CBC-derived inflammatory indices was independently associated with a higher prevalence of obesity. RCS regression analyses revealed non-linear associations of CBC-derived inflammatory indices with CVD and all-cause mortality in obese individuals. Furthermore, RSF models identified the [neutrophils + monocytes]/lymphocytes ratio (NMLR) as the most important predictor of all-cause mortality. Conclusion: These analyses revealed that high CBC-derived inflammatory biomarker levels were linked to an increase in the prevalence of both general and abdominal obesity. Among obese individuals, the relationship between elevated CBC-derived inflammatory biomarker levels and both CVD and all-cause mortality conformed to a non-linear “U” shape. Furthermore, NMLR emerged as the most relevant predictor for all-cause mortality
IL18 is a Prospective Target Affecting Radioiodine Therapy Sensitivity and Prognosis in Differentiated Thyroid Carcinoma
No full textBackground: Differentiated Thyroid Carcinoma (DTC) presents diverse patient outcomes, highlighting the need to identify reliable prognostic biomarkers. This study focuses on the role of interleukins, particularly interleukin18 (IL18), in predicting survival rates and treatment responses among DTC patients. Methods: We conducted a comprehensive analysis of the association between various pyroptosis-related genes (IL18, IL1A, IL6, Granzyme A (GZMA), and Neutrophil elastase (ELANE)) and overall survival in DTC. The study employed univariate and multivariate Cox models to assess the prognostic value of these cytokines. Additionally, a nomogram model was created, integrating clinical characteristics to improve the precision of predicting patient outcomes. IL18 expression levels in DTC tissues compared to normal tissues were examined, along with their association with patient survival and response to radioactive iodine (RAI) therapy. Results: IL18 emerged as a significant protective factor associated with better survival outcomes, exhibiting higher expression levels in DTC tissues compared to normal tissues. However, its expression was notably lower in RAI-refractory or high-risk groups. This study also identified axitinib as a potential therapeutic agent for high-risk DTC cases, supported by drug prediction analysis. Furthermore, immune cell analysis linked high IL18 expression with an abundance of specific T cells, indicating its involvement in regulating the immune response and influencing the effectiveness of RAI treatment. Conclusions: IL18 holds promise as a prognostic biomarker in DTC, offering valuable insights into patient survival and potential treatment pathways. This study emphasizes the importance of combining molecular and clinical data to improve prognostic models and therapeutic strategies, highlighting the need for further research into the mechanisms of action of IL18 in DTC