ABSTRACT
5-hydroxymethyl-2-furfural (5-HMF) is a by-product of Maillard reaction and widely exists in food and environment, which may lead to lung cancer. However, the relevant mechanism is unknown. This study aims to predict the key targets of 5-HMF-induced lung cancer through network toxicology, analyze the relationship between the key targets and lung cancer through network informatics, and further validate them through in vitro experiments. By using ChEMBL, STITCH, GeneCards, and OMIM databases, 51 toxic targets were identified. GO and KEGG enrichment analyses indicated a strong correlation between toxic targets and lung cancer. Through protein-protein interaction (PPI) analysis, MAPK3, MAPK1, and SRC were identified as key targets implicated in 5-HMF-induced lung cancer. The HPA database showed high expression of these three key targets in lung cancer tissues. Kaplan-Meier database demonstrated that the higher expression of these key targets in lung cancer patients was associated with a poorer prognosis. The TIMER database revealed that the high expression of these key targets had a significant impact on the level of immune cell infiltration in lung cancer, particularly impacting CD4+ T cells and macrophages. Finaly, in In vitro experiments demonstrated that prolonged exposure to 5-HMF induced malignant transformation of BEAS-2B cells and the upregulation of key targets. The findings suggest that 5-HMF is a contributing factor in the development of lung cancer, with MAPK3, MAPK1, and SRC potentially playing crucial roles in this process.
ABSTRACT
BACKGROUND: Polypharmacy is common in older adults with psychiatric disorders, but no consensus has reached about the reliable indicators evaluating the benefits and risks of drug-drug interactions (DDIs) in polypharmacy. We aimed to identify indicators suitable for evaluating the clinical significance of DDIs in polypharmacy in older adults with psychiatric disorders. METHODS: The online tools were used to distribute and collect the questionnaires. The Delphi method was applied to analyze experts' opinions. The degree of authority and coordination of experts were analyzed using the coefficient of variation, coefficient of coordination, expert's judgment factor, familiarity with the study content factor, and Kendall coordination coefficient. Statistical analysis was conducted using the IBM SPSS® Statistics Package version 26.0. RESULTS: After three rounds of expert consultation, five primary and eleven secondary indicators were identified. The primary "pharmacodynamic indicator" included "severity of adverse drug reactions", "duration of adverse drug reaction", "symptom relief", "time to onset of symptomatic relief", "number of days in hospital", and "duration of medication". The secondary "pharmacokinetic indicator" contained "dosage administered" and "dosing intervals". The primary "patient tolerance indicator" contained one secondary indicator of "patient tolerability". The primary indicator "patient adherence" contained one secondary indicator of "patient adherence to medication". The primary indicator "cost of drug combination" contained one secondary indicator of "readmission". These indicators were used to determine the clinical significance of DDIs during polypharmacy. CONCLUSIONS: The clinical significance of drug combinations should be taken into account when polypharmacy is used in the elderly. The five primary indicators and eleven secondary indicators might be preferred to evaluate their risks and benefits. Medication management in this population requires a multidisciplinary team, in which nurses play a key role. Future research should focus on how to establish efficient multidisciplinary team workflows and use functional factors to assess DDIs in polypharmacy for psychiatric disorders.
Subject(s)
Delphi Technique , Drug Interactions , Mental Disorders , Polypharmacy , Humans , Mental Disorders/drug therapy , Aged , Male , Female , Drug-Related Side Effects and Adverse Reactions , Middle Aged , Surveys and Questionnaires , Clinical RelevanceABSTRACT
Branches covering (BC) is a way to reuse the pruned branches and save the cost of ground cloth. This study investigated the effects of BC and ground-cloth covering on the soil microcosm environment by measuring the chemical properties and microbial communities at different soil depths for 6 years. The results revealed that BC significantly improved soil chemical properties, increased the abundance of bacterial microbial communities and the diversity and homogeneity of bacteria and fungi, while decreased the abundance of fungal microbial communities. There was a threshold value for the regulation of microbial communities by BC, which decreased the high-abundance communities (Proteobacteria, Ascomycota, etc.) and increased the low-abundance communities (Acidobacteriota, Basidiomycota, etc.). Fungi were more sensitive to BC than bacteria. The stability and homogeneity of microorganisms were stronger in the 15-25 cm soil layer. The bacterial phyla were dominated by Proteobacteria, with the top 10 phyla accounting for more than 80% of the relative abundance; the genera were dominated by MND1, with the top 10 genera accounting for about 10%. The fungal phyla were dominated by Ascomycota, with the top 10 phyla accounting for 50-90%; the genera were dominated by unidentified Pyronemataceae sp., with the top 10 genera accounting for 30-60%. The phyla that differed significantly between treatments were mainly Proteobacteria, Ascomycota, Acidobacteriota, and Basidiomycota. In addition, metabolism was the predominant function in bacteria, while Saprotroph was the predominant function in fungi. Bacteroidota correlated strongly with soil chemical properties and bacterial functions, while Chytridiomycota correlated strongly with soil chemical properties and Pathogen-Saprotroph-Symbiotroph. In conclusion, BC can improve soil nutrient content and optimize microbial community structure and function. Through initially assessing the effects of BC on soil nutrients and microorganisms in pear orchard rows, this study provides a reference for excavating key microorganisms and updating the soil row management model.
ABSTRACT
With the increasing prevalence of microbial infections, which results in prolonged inflammation and delayed wound healing, the development of effective and safe antimicrobial wound dressings of multiple properties remains challenging for public health. Despite their various formats, the available developed dressings with limited functions may not fulfill the diverse demands involved in the complex wound healing process. In this study, multifunctional sandwich-structured electrospinning nanofiber membranes (ENMs) were fabricated. According to the structural composition, the obtained ENMs included a hydrophilic inner layer loaded with curcumin and gentamicin sulfate, an antibacterial middle layer consisting of bovine serum albumin stabilized silver oxide nanoparticles, and a hydrophobic outer layer. The prepared sandwich-structured ENMs (SNM) exhibited good biocompatibility and killing efficacy on Escherichia coli, Staphylococcus aureus, and Methicillin-resistant S. aureus (MRSA). In particular, transcriptomic analysis revealed that SNM inactivated MRSA by inhibiting its carbohydrate and energy metabolism and reduced the bacterial resistance by downregulating mecA. In the animal experiment, SNM showed improved wound healing efficiency by reducing the bacterial load and inflammation. Moreover, 16S rDNA sequencing results indicated that SNM treatment may accelerate wound healing without observed influence on the normal skin flora. Therefore, the constructed sandwich-structured ENMs exhibited promising potential as dressings to deal with the infected wound management.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Nanofibers , Animals , Anti-Bacterial Agents/chemistry , Nanofibers/chemistry , Methicillin Resistance , Inflammation/drug therapyABSTRACT
BACKGROUND: Inflammatory disorders of the breast (IDB) damages the interests of women and children and hinders the progress of global health seriously. Several studies had offered clues between gut microbiota (GM) and inflammatory disorders of the breast (IDB). The gut-mammary gland axis also implied a possible contribution of the GM to IDB. However, the causality between them is still elusive. METHODS: The data of two-sample Mendelian randomization (MR) study related to the composition of GM (n = 18,340) and IDB (n = 177,446) were accessed from openly available genome-wide association studies (GWAS) database. As the major analytical method, inverse variance weighted (IVW) was introduced and several sensitive analytical methods were conducted to verify results. RESULTS: Inverse variance weighted revealed Eubacterium rectale group (OR = 1.87, 95% CI: 1.02-3.43, p = 4.20E-02), Olsenella (OR = 1.29, 95% CI: 1.02-1.64, p = 3.30E-02), Ruminiclostridium-6 (OR = 1.53, 95% CI: 1.08-2.14, p = 1.60E-02) had an anti-protective effect on IDB. Peptococcus (OR = 0.75, 95% CI: 0.60-0.94, p = 1.30E-02) had a protective effect on IDB. The results were credible through a series of test. CONCLUSIONS: We revealed causality between IDB and GM taxa, exactly including Ruminiclostridium-6, Eubacterium rectale group, Olsenella and Peptococcus. These genera may become novel biomarkers and supply new viewpoint for probiotic treatment. However, these findings warrant further test owing to the insufficient evidences.
Subject(s)
Actinobacteria , Gastrointestinal Microbiome , Probiotics , Child , Female , Humans , Gastrointestinal Microbiome/genetics , Genome-Wide Association Study , Evidence GapsABSTRACT
Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , ErbB Receptors/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Drug Resistance, Neoplasm , Cell Line, TumorABSTRACT
Due to the misuse of antibiotics, the emerging drug-resistance of pathogenic microbes has aroused considerable concerns for the public health, which demands the continuous search for safe and efficient antimicrobial treatment. In this study, curcumin reduced and stabilized silver nanoparticles (C-Ag NPs) were successfully encapsulated into electrospun nanofiber membranes consisted of polyvinyl alcohol (PVA) cross-linked by citric acids (CA), which exhibited desirable biocompatibility and broad-spectrum antimicrobial activities. The homogeneously distributed and sustained release of C-Ag NPs in the constructed nanofibrous scaffolds yield prominent killing effect against Escherichia coli, Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA), which involved the reactive oxygen species (ROS) generation. Outstanding elimination of bacterial biofilms and excellent antifungal activity against Candida albicans was also identified after treated with PVA/CA/C-Ag. Transcriptomic analysis on MRSA treated by PVA/CA/C-Ag revealed the antibacterial process is related to disrupting carbohydrate and energy metabolism, as well as destroying bacterial membranes. Significant down-regulation of the expression of multidrug-resistant efflux pump gene sdrM was observed pointing to the role of PVA/CA/C-Ag to overcome the bacterial resistance. Therefore, the constructed ecofriendly and biocompatible nanofibrous scaffolds provide a robust and versatile nanoplatform of reversal potential to eradicate drug-resistant pathogenic microbe in environmental as well as healthcare applications.
Subject(s)
Anti-Infective Agents , Curcumin , Metal Nanoparticles , Methicillin-Resistant Staphylococcus aureus , Nanofibers , Curcumin/pharmacology , Silver/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity TestsABSTRACT
Objective: 5-Hydroxymethylfurfural (5-HMF) is an important component of air pollution, confirmed to be a risk factor for pulmonary inflammation. However, its association with general health is unknown. This article aimed to clarify the effect and mechanism of 5-HMF in the occurrence and aggravation of frailty in mice by investigating whether exposure to 5-HMF was linked to the occurrence and aggravation of mice frailty. Methods: Twelve male C57BL/6 mice (12-month-old, 38 ± 1 g) were randomly divided into the control group and the 5-HMF group. The 5-HMF group was treated with 5-HMF (1 mg/kg/day, respiratory exposure) for 12 months, whereas the control group was treated with equal amounts of sterile water. After the intervention, the ELISA method was used to detect the serum inflammation level of the mice, and the physical performance and frail status were evaluated using a Fried physical phenotype-based assessment tool. The differences in the body compositions were calculated from their MRI images, and the pathological changes in their gastrocnemius muscle were revealed using the H&E staining. Furthermore, the senescence of skeletal muscle cells was evaluated by measuring the expression levels of senescence-related proteins by the western blotting. Results: In the 5-HMF group, serum inflammatory factors IL-6, TNF-α, and CRP levels were significantly raised (p < 0.01). Mice in this group had higher frailty scores and significantly reduced grip strength (p < 0.001), slower weight gains, less WVgastrocnemius muscle masses, and lower sarcopenia indices (SI). In addition, the cross-sectional areas of their skeletal muscles were reduced, and the levels of their cell senescence-related proteins (p53, p21, p16, SOD1, SOD2, SIRT1, SIRT3) were considerably altered (p < 0.01). Conclusion: 5-HMF may induce chronic and systemic inflammation, which in turn accelerates the progression of the frailty of mice through cell senescence.
ABSTRACT
Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.
Subject(s)
Prostatic Neoplasms , Humans , Male , Solubility , Prostatic Neoplasms/drug therapyABSTRACT
AIMS: Although synthetic ZnO nanoparticles (Nano-ZnO) as an alternative of ZnO compounds have been extensively used such as in livestock production, the increased consuming of Nano-ZnO has raised considerable concerns in environmental pollution and public health. Because of the low digestion of Nano-ZnO, the systematic studies on their interactions with gut microbiota remain to be clarified. MATERIALS AND METHODS: Nano-ZnOs were prepared by co-precipitation (ZnO-cp) and high temperature thermal decomposition (ZnO-td) as well as the commercial type (ZnO-s). Transmission electron microscopy (TEM) was used to monitor the morphology of Nano-ZnO. CCK-8 assay was used for cytotoxicity evaluation. Total antioxidant capacity assay, total superoxide dismutase assay, and lipid peroxidation assay were used to evaluate oxidative states of rats. 16S rRNA was used to study the impact of Nano-ZnO on the rat gut microbiome. KEY FINDINGS: Both ZnO-cp and ZnO-td exhibited low cytotoxicity while ZnO-s and ZnO-td exhibited prominent antibacterial activities. After a 28-day oral feeding with 1000 mg/kg Zn at dietary dosage, ZnO-s showed slight effect on causing oxidative stress in comparison with that of ZnO-cp and ZnO-td. Results of 16S rRNA sequencing analysis indicated that ZnO-td as a promising short-term nano-supplement can increase probiotics abundances like strains belonged to the genus Lactobacillus and provide the antipathogenic effect. SIGNIFICANCE: The results of the gut microbiome alteration by synthetic Nano-ZnO not only provide solution to exposure monitoring of environmental hazard, but rationalize their large-scale manufacture as alternative additive in the food chain.
Subject(s)
Gastrointestinal Microbiome , Nanoparticles , Zinc Oxide , Rats , Animals , Zinc Oxide/toxicity , RNA, Ribosomal, 16S/genetics , Dietary Exposure , Nanoparticles/toxicityABSTRACT
Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD50 > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.
Subject(s)
Breast Neoplasms , Cyclin-Dependent Kinase 6 , Female , Humans , Cyclin-Dependent Kinase 4 , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistryABSTRACT
Growing evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in various human tumors. LncRNA LINC00659 (LINC00659) is a newly identified lncRNA and its roles in tumors remain largely unclear. In this study, we elucidated the potential functions and molecular mechanisms of LINC00659 on the biological behaviors of gastric cancer (GC), and also explored its clinical significance. We firstly demonstrated that LINC00659 levels were distinctly up-regulated in both GC specimens and cells using bioinformatics analysis and RT-PCR. The results of ChIP assays and luciferase reporter assays confirmed that upregulation of LINC00659 was activated by SP1 in GC. Clinical assays revealed that higher levels of LINC00659 were associated with TNM stage, lymphatic metastasis, and poorer prognosis. Moreover, LINC00659 was confirmed to be an independent prognostic marker for the patients with GC using multivariate assays. Lost-of-function assays indicated that knockdown of LINC00659 suppressed the proliferation, metastasis, and EMT progress of GC cells in vitro. Mechanistic investigation indicated that LINC00659 served as a competing endogenous RNA (ceRNA) for miR-370, thereby resulting in the upregulation of leading to the depression of its endogenous target gene AQP3. Overall, our present study revealed that the LINC00659/miR-370/AQP3 axis contributes to GC progression, which may provide clues for the exploration of cancer biomarkers and therapeutic targets for GC.
Subject(s)
Aquaporin 3 , MicroRNAs , RNA, Long Noncoding , Sp1 Transcription Factor , Stomach Neoplasms , Aquaporin 3/genetics , Aquaporin 3/metabolism , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Up-RegulationABSTRACT
BACKGROUND: Polypharmacy increases the risk of potential drug-drug interactions (pDDIs). This retrospective analysis was conducted to detect pDDIs and adverse drug reactions (ADRs) among older adults with psychiatric disorder, and identify pDDIs with clinical significance. METHODS: A retrospective analysis was carried out based on the medical records of older adults with psychiatric disorders. Data on demographic characteristics, substance abuse, medical history, and medications were extracted. The Lexi-Interact online database was used to detect pDDIs. The minimal clinically important difference (MCID) was set as the change in the Treatment Emergent Symptom Scale (TESS) score between admission and discharge. The median and interquartile ranges were used for continuous variables, and frequencies were calculated for dichotomous variables. Poisson regression was implemented to determine the factors influencing the number of ADR types. The influencing factors of each ADR and the clinical significance of the severity of the ADR were analysed using binary logistic regression. P < 0.05 was considered statistically significant. RESULTS: A total of 308 older adults were enrolled, 171 (55.52%) of whom had at least 1 pDDI. Thirty-six types of pDDIs that should be avoided were found, and the most frequent pDDI was the coadministration of lorazepam and olanzapine (55.5%). A total of 26 ADRs induced by pDDIs were identified, and the most common ADR was constipation (26.05%). There was a 9.4 and 10.3% increase in the number of ADR types for each extra medical diagnosis and for each extra drug, respectively. There was a 120% increase in the number of ADR types for older adults hospitalized for 18-28 days compared with those hospitalized for 3-17 days. There was an 11.1% decrease in the number of ADR types for each extra readmission. The length of hospitalization was a risk factor for abnormal liver function (P < 0.05). The use of a large number of drugs was a risk factor for gastric distress (P < 0.05) and dizziness and fainting (P < 0.05). None of the four pDDIs, including coadministrations of olanzapine and lorazepam, quetiapine and potassium chloride, quetiapine and escitalopram, and olanzapine and clonazepam, showed clinical significance of ADR severity (P > 0.05). CONCLUSIONS: pDDIs are prevalent in older adults, and the rate is increasing. However, many pDDIs may have no clinical significance in terms of ADR severity. Further research on assessing pDDIs, and possible measures to prevent serious ADRs induced by DDIs is needed to reduce the clinical significance of pDDIs.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Mental Disorders , Aged , Drug Interactions , Drug-Related Side Effects and Adverse Reactions/epidemiology , Humans , Lorazepam , Mental Disorders/drug therapy , Olanzapine , Quetiapine Fumarate , Retrospective StudiesABSTRACT
Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.
ABSTRACT
Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.
Subject(s)
Prostatic Neoplasms , Humans , Male , Phosphorylation , Prostatic Neoplasms/drug therapy , TyrosineABSTRACT
Preeclampsia remains a high cause of incidence and death for mothers and fetuses in developing nations. Preeclampsia has numerous clinical and biochemical markers that have been tested, but they have failed to provide a conclusive diagnosis in the different phases of the disease's progression. Herein, our team intended to determine potential diagnostic biomarkers for preeclampsia and analyzed associations with immune cells. Two microarray data from mankind's preeclampsia and control specimens were acquired from GSE75010 and GSE44711 datasets. Differentially expressed genes (DEGs) were identified between77 normal samples and 80 preeclampsia samples. Candidate biomarkers were discovered using the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) analysis. The expressions and diagnostic values of genes in preeclampsia were further demonstrated in the GSE44711 dataset (8 control samples and 8 preeclampsia samples). The correlation of critical genes with the proportion of immune cells was analyzed. We identified 20 DEGs in preeclampsia. Diseases enriched by DEGs were mainly related to preeclampsia, gestational diabetes, ovarian disease, female reproductive system disease, and endocrine system disease. COL17A1, FLT1, FSTL3, and SERPINA3 were identified as diagnostic genes of preeclampsia and validated in the GSE44711 datasets. Immune cell infiltration assays suggested that COL17A1, FLT1, FSTL3, and SERPINA3 were related to several immune cells. Overall, we identified four critical diagnostic genes in preeclampsia. Furthermore, more well-designed research studies with larger cohorts were warranted to confirm the value of the four genes for the diagnosis and outcome of preeclampsia patients.
Subject(s)
Follistatin-Related Proteins , Pre-Eclampsia , Biomarkers/metabolism , Female , Humans , Pre-Eclampsia/diagnosis , Pre-Eclampsia/genetics , PregnancyABSTRACT
Objective: This study conducted a comprehensive analysis of the members of the PTPN family and emphasized the key role of PTPN2 as a potential therapeutic target and diagnostic biomarker in improving the survival rate of PAAD. Method: Oncomine was used to analyze the pan-cancer expression of the PTPN gene family. The Cancer Genome Atlas (TCGA) data as well as Genotype-Tissue Expression (GTEx) data were downloaded to analyze the expression and prognosis of PTPNs. The diagnosis of PTPNs was evaluated by the experimental ROC curve. The protein-protein interaction (PPI) network was constructed by combining STRING and Cytoscape. The genes of 50 proteins most closely related to PTPN2 were screened and analyzed by GO and KEGG enrichment. The differentially expressed genes of PTPN2 were found by RNA sequencing, and GSEA enrichment analysis was carried out to find the downstream pathways and targets, which were verified by online tools and experiments. Finally, the relationship between PTPN2 and immune cell infiltration in PAAD, and the relationship with immune score and immune checkpoint were studied. Result: The expression patterns and the prognostic value of multiple PTPNs in PAAD have been reported through bioinformatic analyzes. Among these members, PTPN2 is the most important prognostic signature that regulates the progression of PAAD by activating JAK-STAT signaling pathway. Comparison of two PAAD cell lines with normal pancreatic epithelial cell lines revealed that PTPN2 expression was up-regulated as a key regulator of PAAD, which was associated with poor prognosis. Knockdown of PTPN2 caused a profound decrease in PAAD cell growth, migration, invasion, and induced PAAD cell cycle and apoptosis. In addition, we conducted a series of enrichment analyses to investigate the PTPN2-binding proteins and the PTPN2 expression-correlated genes. We suggest that STAT1 and EGFR are the key factors to regulate PTPN2, which are involved in the progression of PAAD. Meanwhile, the silencing of PTPN2 induced the repression of STAT1 and EGFR expression. Conclusion: These findings provide a comprehensive analysis of the PTPN family members, and for PAAD, they also demonstrate that PTPN2 is a diagnostic biomarker and a therapeutic target.
Subject(s)
Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Apoptosis/genetics , Cell Cycle/genetics , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Adenocarcinoma/secondary , Biomarkers, Tumor/genetics , Cell Proliferation , Gene Expression Profiling , Humans , Neoplasm Metastasis , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/secondary , Prognosis , Transcriptome , Up-RegulationABSTRACT
Despite the extensive uses of ZnO nanoparticles as promising antimicrobial agents to tackle the severe microbial infections, the systematic antibacterial studies on ZnO nanoparticles with manipulable nanoscale morphologies at the genetic expression level remain ill-defined. In this study, via a controllable thermal decomposition, ZnO nanoparticles of different morphologies were facilely prepared. Additionally, the surface PEGylation of ZnO was conducted to obtain the nanoparticles of low biotoxicity. While all the prepared ZnO nanoparticles exhibited the significantly chemical activities, the pronounced antibacterial effect of obtained ZnO nanoparticles was also identified, in which the ultra-small ones (~5 nm) showed the best performance. Moreover, the antibacterial activities of ZnO nanoparticles were studied by bacterial nucleic acid leakage, alkaline phosphatase, biofilm and reactive oxygen species (ROS) assays. Furthermore, the transcriptome analysis of ZnO nanoparticles with different morphologies against Escherichia coli (E. coli) revealed the underlying antibacterial mechanism involved the signal transduction, material transport, energy metabolism and other biological processes. Therefore, the cost-effective preparation of ZnO nanoparticles with distinct morphological features provides insights for the development of application specific antibacterial agents.
Subject(s)
Nanoparticles , Zinc Oxide , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biofilms , Escherichia coli , Microbial Sensitivity Tests , Nanoparticles/chemistry , Zinc Oxide/chemistry , Zinc Oxide/pharmacologyABSTRACT
Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.