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NELL1 Growth Factor Suppresses the NF-κB Signaling Pathway During Orthodontic Tooth Movement and Attenuates the Inflammatory Response
No full textBackground: Exogenous Nel-like molecule type 1 (NELL1) is a viable alternative in orthodontics and other fields due to its osteogenic and angiogenic properties. This study aimed to elucidate the role of NELL1 in the inflammatory response elicited by orthodontic tooth movement (OTM), providing insights into the mechanisms behind this response and establishing a theoretical foundation for the utilizing NELL1 as a therapeutic option. Methods: Human periodontal ligament (hPDL) cells obtained from clinical samples were divided into three groups: control, compressive forces (CF), and CF+ NELL1. Inflammatory factors (cyclooxygenase 2 (COX2), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β)) were measured using real-time quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Culture supernatants were co-cultured with THP-1 cells to assess macrophage differentiation. Immunoblotting and Co-Immunoprecipitation (Co-IP) assays were employed to investigate the molecular mechanism of NELL1 in hPDL cells. Results: In comparison to the CF group, the CF+ NELL1 group exhibited reduced mRNA levels and production of inflammatory factors, including COX2, IL-6, IL-8, TNF-α, iNOS, and IL-1β (p < 0.05, p < 0.01, p < 0.001, and p < 0.0001) and reduced macrophage activation (p < 0.05). Immunoblotting assays showed that NELL1 could inhibit the activation of the nuclear factor-kappa B (NF-κB) signaling pathway, consequently regulating the expression of inflammatory factors (p < 0.0001, p < 0.05, p < 0.05, and p < 0.01). Co-Immunoprecipitation (Co-IP) results confirmed the intermolecular interaction between NELL1 and inhibitor of kappa B kinase (IKK), and overexpression of IKK in hPDL cells could reduce the anti-inflammatory effect of NELL1 following CF treatment (p < 0.01, p < 0.001, and p < 0.0001). Conclusions: NELL1 presents a promising therapeutic option to inhibit the activation of the NF-κB signaling pathway by preventing phosphorylation and reducing the inflammatory response during the orthodontic tooth movement
Inhibitory Effect of KIOM-2015EW, a Water Extract of Acer Palmatum Thumb, on PCSK9 Expression in a Fructose-Induced in Vitro Fatty Liver Model
No full textBackground: Acer Palmatum Thumb is a traditional medicinal herb used in East Asia, and previous studies performed by our team revealed the anti-inflammatory and neuroprotective effects of KIOM-2015EW, a water extract of Acer Palmatum Thumb leaves. Hence, this study aimed to explore the inhibitory effects of KIOM-2015EW on decreasing proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in a fructose-induced fatty liver model. Method: HepG2, a human hepatocyte-derived hepatocellular carcinoma, was exposed to low-glucose Dulbeccos modified Eagles medium (DMEM) media with or without fructose, statins, and KIOM-2015EW. Cell viability was measured by cell counting kit-8 (CCK-8) analysis, and fat accumulation and low-density lipoprotein (LDL) uptake were, respectively, detected by oil-red O staining and LDL-uptake assay. The mRNA and protein levels of PCSK9, low-density lipoprotein receptor (LDLR), peroxisome proliferator-activated receptor alpha (PPARα), and retinoid X receptor alpha (RXRα) were measured via real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. PCSK9 transcription factors were predicted via chemical-protein interactions using the Stichi database. Result: KIOM-2015EW significantly decreased fat accumulation and recovered LDL uptake in fructose-induced cells (p < 0.05). That also decreased PCSK9 levels induced by fructose or fructose/lovastatin (p < 0.05) and recovered LDLR mRNA expression. Chemical-protein interactions showed that eleven transcription factors (TFs) interacted with two major compounds of KIOM-2015EW. Inhibition of PPARα/RXRα and mitogen-activated protein kinase (p38) significantly attenuated PCSK9 expression induced by fructose. KIOM-2015EW decreased PPARα and RXRα expression which was increased by fructose and fructose/statin (p < 0.05). Conclusion: This study suggested that KIOM-2015EW may lower serum cholesterol, and it can be used as a natural substance for the prevention or treatment of hypercholesterolemia
Bioinformatics Analysis, ceRNA Network Construction and Prediction of Potential Therapeutic Drug Effects Based on TCGA and CMap Datasets in Endometrial Cancer
No full textBackground: Uterine Corpus Endometrial Carcinoma (UCEC) ranks second among most common gynecological tumors, and the overall treatment situation is inadequate. In-depth study of tumorigenesis mechanism and the discovery of effective therapeutic drugs are an urgent problem to be solved. Our study mainly focused on the construction of competing endogenous RNA (ceRNA) network and the exploration of potential treatment strategies of UCEC. Methods: 35 normal and 543 endometrial cancer samples had RNA expression profile extracted from The Cancer Genome Atlas (TCGA) GDC data portal. DEGs of LncRNAs (DELncRNAs), DEGs of miRNAs (DEmiRNAs) and DEGs of mRNAs (DEmRNAs) were calculated by R software (version 4.2.1). The function of DEmRNAs was analyzed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction (PPI) network and long non-coding RNA (LncRNA)-microRNA (miRNA)-mRNA regulation network were constructed. Further evaluation included venn analysis for vital protein and prediction of potential drugs were based on Connectivity Map (CMap). Lastly, we verified the cyclin B1 (CCNB1) as a potential therapeutic target with wet experiment (western blotting, clonogenic assay and flow cytometry). Results: Our results revealed that 1218 DELncRNAs, 187 DEmiRNAs and 1897 DEmRNAs were identified by comparing UCEC tissue with normal controls. A total of 106 DELncRNAs, 27 DEmiRNAs and 56 DEmRNAs were included to construct a ceRNA network. GO analysis revealed that upregulated mRNAs were involved in nuclear division process. CCNB1 was included in both hub genes of PPI network and ceRNA network, which might be a powerful potential therapeutic target. We predicted 10 potential compounds based on ceRNA network and 49 potential compounds based on DEmRNAs. Aminopurvalanol-a, purvalanol-a and AZD-8055 were candidate compounds most likely to have therapeutic effect. Based on the TCGA database, we successfully constructed a PPI network and ceRNA network. Downregulation of CCNB1 markedly suppressed the proliferation ability and promoted the apoptosis of the UCEC cell lines (p < 0.001). Conclusions: We demonstrated that CCNB1, a gene involved in multiple bioinformatic models, is considered to be a potential therapeutic target for endometrial cancer. Aminopurvalanol-a, purvalanol-a and AZD-8055 are the three most potential therapeutic drugs for UCEC
Overexpression of Tripartite Motif Containing 37 Induces Cisplatin Resistance to Ovarian Carcinoma and Activates the Wnt/β-Catenin Signaling Pathway
No full textBackground: Expression confusion of tripartite motif (TRIM) family proteins has been associated with various cellular processes such as immune disorders, neurological-related diseases, protein degradation, and tumorigenesis. Therefore, we aim to explore the function and clinical significance of TRIM family proteins in chemotherapy resistance in ovarian cancer. Methods: Western blot analysis and immunohistochemistry (IHC) assay were conducted to assess the protein expression levels of TRIM37 in both ovarian cancer cell lines and patient tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were conducted to detect the effect of TRIM37 on 50% inhibitory concentration (IC50). The rate of apoptotic cells was conducted using fluorescence-activated cell sorting (FACS) assays. Moreover, Luciferase assays were performed to detect the luciferase reporter activity. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were conducted to detect the pro-cancer effect of TRIM37. Results: We found that TRIM37 was increased in ovarian cancer tissues, showing partial response to cisplatin chemotherapy (p < 0.01). The high TRIM37 expression was linked to a worse overall survival prognosis and lower disease-free survival rate in our cancer tissue samples and public ovarian cancer databases (p < 0.001, p < 0.01). Functionally, overexpression of TRIM37 endows cisplatin resistance in ovarian cancer cells. However, inhibition of TRIM37 counteracted this resistance in ovarian cancer. Additionally, TRIM37 was found to activate the wnt/β-catenin signaling pathway. Conclusions: Our findings indicate that TRIM37 contributes to enhanced cisplatin resistance in ovarian cancer, suggesting its potential as a promising chemotherapy biomarker
Dexmedetomidine Affects Triple-Negative Breast Cancer by Targeting IDO1 and CHRM3
No full textBackground: Triple-negative BrCa (TNBC) has been recognized as the most invasive type of breast cancer (BrCa), posing the worst outcomes with a minimal overall survival rate. The use of dexmedetomidine potentially affected BrCa surgery and dexmedetomidine was reported to have direct effects on TNBC cells. Therefore, this study aimed to explore the mechanisms underlying the effect of dexmedetomidine on TNBC. Methods: Through bioinformatic analysis, dexmedetomidine targets were predicted using The Cancer Genome Atlas data and SwissTargetPrediction database. These targets were validated in TBNC using both clinical samples and cell lines (MDA-MB-231, MCF7, and MCF10A). The cancer cell lines, and normal breast cell lines were divided into cancer and normal groups. Both groups were exposed to dexmedetomidine treatment. Furthermore, silencing and overexpression experimental models were used to determine the effect of dexmedetomidine treatment. Expression levels of target genes and their proteins were evaluated using qRT-PCR, western blot analysis, and immunohistochemistry. Cell Counting Kit-8 was used to determine the effect of dexmedetomidine on cells with target silencing. The binding model of the candidate targets was docked, and critical amino acids were mutated to validate the binding model. Results: Dexmedetomidine selectively inhibited cancer cells. Catalytic subunit of the DNA-dependent protein kinase (PRKDC), indoleamine 2,3-dioxygenase 1 (IDO1), opioid receptor kappa 1 (OPRK1), glutaminyl-peptide acyltransferase (QPCT), macrophage migration inhibitory factor (MIF), potassium voltage-gated channel subfamily H (Eag-related) member 2 (KCNH2), cholinergic receptor muscarinic 3 (CHRM3), and potassium intermediate/small conductance calcium-activated channel subfamily N member 4 (KCNN4) were identified as dexmedetomidine targets in TNBC. The expression levels of PRKDC, IDO1, MIF, KCNH2, CHRM3, and KCNN4 were found to be upregulated in TNBC tissues compared to the non-TNBC tissues (p < 0.05). Silencing of these genes reduced the sensitivity of TNBC cells to dexmedetomidine (p < 0.05). However, this effect was counteracted when the silenced genes were overexpressed, increasing the sensitivity of cells to dexmedetomidine (p < 0.05). Furthermore, a direct interaction of dexmedetomidine with IDO1 and CHRM3 was observed, impacting the sensitivity of cells to dexmedetomidine (p < 0.05). Conclusion: IDO1 and CHRM3 are direct targets of dexmedetomidine in TNBC
The Effects of β-Cyclodextrin on Rat Heart Rate, Systole, Diastole, and the Underlying Mechanisms
No full textBackground: DL-3-n-Butylphthalide (NBP) sodium chloride injection is widely used in treating cerebral ischemia stroke, yet it may lead to adverse effects, including a reduction in heart rate (HR). However, the specific component responsible for affecting cardiac function remains unclear. Aim: This study aimed to elucidate the component of NBP that affects cardiac function and delineate its mechanisms of action. Methods: The Langendorff perfusion system was employed to investigate the effects of NBP and its principal components on the functional parameters of isolated rat hearts. The apoptosis/necrosis assay kit evaluated the impact of β-cyclodextrin (β-CD) on cardiomyocyte apoptosis and necrosis. Furthermore, Di-8-ANEPPS staining was performed to visualize T-tubule disruptions. Finally, patch clamp techniques were employed to examine alterations in L-type calcium channel function. Results: β-CD, rather than butylphthalide, impaired cardiac function. Higher concentrations or longer perfusion times of β-CD resulted in significant reductions in HR (p < 0.05). Moreover, increased concentrations or longer perfusion time of β-CD led to elevated left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) (p < 0.05). β-CD perfusion also decreased the maximal left ventricular pressure rising rate (dp/dt max) and -dp/dt max (p < 0.05). Treatment with different concentrations of β-CD significantly decreased B-cell lymphoma-2 associated X protein (Bax) expression levels and increased cardiomyocyte apoptosis and necrosis rates (p < 0.01). Pre-treatment and post-treatment with cholesterol significantly mitigated β-CD-induced cardiomyocyte necrosis, with post-treatment exhibiting a stronger effect than pre-treatment (p < 0.05). Di-8-ANEPPS staining revealed the stronger concentration-dependent disruption of T-tubule integrity and continuity following β-CD treatment. Furthermore, paracellular administration of β-CD did not alter the current density or activation curve trend of L-type calcium channels but caused a rightward shift in the activation curve. Conclusion: β-CD, a principal component of NBP, induces a reduction in HR, which depends on the concentration and duration of β-CD treatment. The mechanism underlying this effect may involve cardiomyocyte necrosis, T-tubule damage, and modulation of L-type calcium channel function
Pan-Virome of Third Wave SARS-CoV-2 Strains in Pakistan Reveals Higher Entropy
No full textBackground: Pakistan faced five distinct waves of COVID-19 caused by unique SARS-CoV-2 strains. Of these, the third wave, which started in March 2021 and ended in June 2021, proved worst causing 335,728 reported infections and 7849 deaths. During the third wave SARS-CoV-2 alpha variant remained dominant causing more than seventy percent of infections. Hence, the current study aimed to investigate the entropy rate in SARS-CoV-2 through pan-virome analysis during the third wave of COVID-19 in Pakistan. Methods: Whole-genome sequencing of five viral isolates (three from female and two from male patients) was performed and in-silico analysis was carried out by taking into account other reported worldwide sequences. Bioinformatics analysis was done, and a phylogenetic tree was constructed to find out the clustering. Prokka was utilized to predict the genes and annotate all the viromes. The pan-genome of SARS-CoV-2 was inferred with Snippy. Results: The phylogenetic analysis reveals that most of the genomes were identical. It was discovered that the most common change was C > T, whereas T > A substitutions were the rarest. There was a total of nine different types of mutations and four types of mutations had a significant impact on phenotypes. The four specific types of mutations identified in our study have been observed to lead to notable changes in the genetic makeup of the SARS-CoV-2 virus. Such mutations suggested a high entropy in the pan-virome of third wave SARS-CoV-2 strains. Conclusion: This research provides valuable insights into unique SARS-CoV-2 strains and dominant variants during the third wave in the country. The phylogenetic tree and virome annotation revealed in tracking transmission patterns. These research efforts contribute to global endeavors in controlling the COVID-19 pandemic and preparing for future viral outbreaks
Robot-assisted coronary surgery: A narrative review on the available data
Get PDFThe robot-based approach has been the most significant advancement in minimally invasive surgery over the past decade. Robotic coronary heart surgery represents half of the total cases of robotics-based cardiac surgery. Since 1998, it has emerged as a revolutionary approach to standard coronary surgery. However, despite its promising beginning, there has been a growing interest in the application of robotics in surgical fields other than cardiac surgery, such as urology and general surgery. In various waves of enthusiasm, single pioneers or visionary cardiac surgeons have tried to extend robotic surgery to different heart procedures, but they still struggled to practice it as a routine approach. Over the last 20 years, robotic platforms have gained importance in minimally invasive heart surgery, with proven safety and efficacy. However, despite its feasibility, safety, and efficacy, less than 0.5%–1.0% of coronary artery bypass grafting procedures are performed using a robot-assisted setup. We believe that in cardiac surgery, the time is ripe to open up new surgical strategies that are increasingly devoted to robotics, hybrid, and augmented-reality-based assistance. With this in mind, we wish to propose an excursus on the state of the art of coronary robotic surgery, its promising results, and its possible future perspectives, with a focus on the most recent achievements. This narrative minireview addresses, therefore, experiences and all aspects related to such a technique, with particular attention gained in robotic coronary revascularization, to the anaesthesiologic as well as surgical aspects, on the learning curve, patient outcome, and related costs, wishing to enlarge the portfolio of the younger generation of cardiac surgeons. In effect, according to the literature data, we are confident that robotic heart surgery is burgeoning, and the new generation of cardiac surgeons must face a gorgeous future if we invest in training and technology
Analysis of the diverse advantages and paths of traditional culture dissemination in online games
Get PDFWith the development of the new media era, factors such as digitization and entertainment are driving changes in the way traditional culture is disseminated. In comparison to traditional distribution media, online games are more vivid, capable of retaining the characteristics of traditional culture while undergoing a livelier transformation and development, and are disseminated in a manner that is widely appealing to the masses. This study, based on the new media characteristics of online games and combined with the current situation of traditional culture dissemination in China and domestic game cases, analyzes the diverse advantages of online games in cultural dissemination, including form, content, promotional methods, and cross-border linkage. It summarizes a dissemination path system starting from three points: cultural resources, game content, and game audience, in order to contribute to the enhancement of the dissemination value of online games and the promotion of contemporary dissemination of traditional culture
Sustainable micro renewal and renovation of arts town in China: Intermingling design of contemporary art and Chinese classical garden
Get PDFThe gardening philosophy of Chinese classical gardens is an integral part of China’s rich traditional culture, reflecting ancient scholars’ understanding of nature and humanity and embodying aesthetic and philosophical values. With the progression of time, integrating the principles of Chinese classical garden gardening into contemporary space design has emerged as a critical issue in contemporary public space design. This study uses the Butong Arts Town in Qinhuangdao as a case study, focusing on applying Chinese classical garden gardening concepts in public space design and regional micro-renovation. Special attention is given to nodes that simultaneously serve interactive and recreational functions. In the micro-renovation of the Butong Arts Town area, Chinese classical garden gardening principles can be employed through greening, landscaping, and other means to enhance the quality of the space. Additionally, by integrating local cultural characteristics, it is possible to create public spaces with distinct regional features, providing a comfortable and pleasant environment for artists, designers, planners, and tourists. The design methods used in this study explore the behavioral characteristics and usage needs of various groups from multiple perspectives, aiming to optimize activity spaces. This research identifies the main issues within the target areas and proposes corresponding improvement measures to enhance the functionality and aesthetic quality of the space. The aim is to integrate people’s growing spiritual pursuits with public activity spaces, providing new references and ideas for future sustainable space design