DPP-4 Inhibitors as Potential Candidates for Antihypertensive Therapy: Improving Vascular Inflammation and Assisting the Action of Traditional Antihypertensive Drugs

Dipeptidyl peptidase-4 (DPP-4) is an important protease that is widely expressed on the surface of human cells and plays a key role in immune-regulation, inflammation, oxidative stress, cell adhesion, and apoptosis by targeting different substrates. DPP-4 inhibitors (DPP-4i) are commonly used as hypoglycemic agents. However, in addition to their hypoglycemic effect, DPP-4i have also shown potent activities in the cardiovascular system, particularly in the regulation of blood pressure (BP). Previous studies have shown that the regulatory actions of DPP-4i in controlling BP are complex and that the mechanisms involved include the functional activities of the nerves, kidneys, hormones, blood vessels, and insulin. Recent work has also shown that inflammation is closely associated with the elevation of BP, and that the inhibition of DPP-4 can reduce BP by regulating the function of the immune system, by reducing inflammatory reactions and by improving oxidative stress. In this review, we describe the potential anti-hypertensive effects of DPP-4i and discuss potential new anti-hypertensive therapies. Our analysis indicated that DPP-4i treatment has a mild anti-hypertensive effect as a monotherapy and causes a significant reduction in BP when used in combined treatments. However, the combination of DPP-4i with high-dose angiotensin converting enzyme inhibitors (ACEI) can lead to increased BP. We suggest that DPP-4i improves vascular endothelial function in hypertensive patients by suppressing inflammatory responses and by alleviating oxidative stress. In addition, DPP-4i can also regulate BP by activating the sympathetic nervous system, interfering with the renin angiotensin aldosterone system (RAAS), regulating Na/H2O metabolism, and attenuating insulin resistance (IR)

Causal association of circulating cholesterol levels with dementia: a mendelian randomization meta-analysis

Prospective studies have shown that abnormally circulating cholesterol is associated with the risk of dementia. However, whether the association is causal or not remains unclear. We attempt to infer the causal association in a MR meta-analysis by using ApoE gene polymorphisms as instrument variables. Studies with dementia risk (27 studies) or circulating lipid levels (7 studies) were included, with totally 3136 dementia patients and 3103 healthy controls. The analyses showed that carriers of ε2 allele significantly were of decreased risk of AD (OR = 0.70; 95% CI: 0.58–0.84; P \u3c 0.01), whereas carriers of ε4 allele were of increased risk of AD (OR = 3.62; 95% CI: 3.03–4.32; P \u3c 0.05), compared to these of ε3 allele. Circulating TC was significantly reduced in carriers of ε2 allele (WMD = − 0.29 mmol/L; 95% CI: −0.54 to −0.03; P \u3c 0.05) and increased in carriers of ε4 allele (WMD = 0.42 mmol/l; 95% CI: 0.001–0.84; P \u3c 0.05). In addition, carriers of ε4 allele had reduction in circulating HDL-C (WMD = − 0.04 mmol/L; 95% CI: − 0.07 to −0.001; P \u3c 0.05). In comparing allele ε2 with ε3, the predicted OR of having AD for 1 mg/dL increment in circulating TC was 0.97 (95% CI: 0.86–0.98; P \u3c 0.05). Comparing allele ε4 with ε3, the predicted OR for a 1 mg/dL increment in TC was 1.08 (95% CI: 1.05–17.58; P \u3c 0.05), and reduction in HDL-C was 2.30 (95% CI: 1.51–43.99; P \u3c 0.05). Our findings demonstrate that high circulating TC and reduced HDL-C levels might be potential risk factors of the development of AD

Population-based case-control study revealed metabolomic biomarkers of suboptimal health status in Chinese population—potential utility for innovative approach by predictive, preventive, and personalized medicine

Background: Suboptimal health status (SHS) is a subclinical stage of chronic diseases, and the identification of SHS provides an opportunity for the predictive, preventive, and personalized medicine (PPPM) of chronic diseases. Previous studies have reported the associations between metabolic signatures and early signs of chronic diseases. Methods: This study aimed to detect the metabolic biomarkers for the identification of SHS in a case-control study. SHS questionnaire-25 (SHSQ-25) was used in a population-based health survey to measure the SHS levels of participants. The liquid chromatography-mass spectrometry-based untargeted metabolomics analysis was conducted on plasma samples collected from 50 SHS participants and 50 age- and sex-matched healthy controls. Results: After adjusting for the confounders, 24 significantly differential metabolites, such as sphingomyelin, sphingosine, sphinganine, progesterone, pregnanolone, and bilirubin, were identified as the candidate biomarkers for SHS. Pathway analysis revealed that sphingolipid metabolism, taurine metabolism, and steroid hormone biosynthesis are the disturbed metabolic pathways related to SHS. A combination of four metabolic biomarkers (sphingosine, pregnanolone, taurolithocholate sulfate, cervonyl carnitine) can distinguish SHS individuals from the controls with a sensitivity of 94.0%, a specificity of 90.0%, and an area under the receiver operating characteristic curve of 0.977. Conclusion: Plasma metabolites are valuable biomarkers for SHS identification, and meanwhile, SHSQ-25 can be used as an alternative health screening tool in the population-based health survey. SHS-related metabolic disturbances could be detected at the early onset of SHS, and SHS-related metabolites could create a window opportunity for PPPM of chronic diseases

Vascular endothelial growth factor and the risk of venous thromboembolism: A genetic correlation and two-sample Mendelian randomization study

Background: The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. Methods: Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran’s Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. Results: LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95 % confidence interval (CI), 1.009 – 1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (β = -0.021, 95 % CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. Conclusions: Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted

Formation, influencing factors, and applications of internal channels in starch: A review

Starch, a natural polymer, has a complex internal structure. Some starches, such as corn and wheat starches, have well-developed surface pores and internal channels. These channel structures are considered crucial in connecting surface stomata and internal cavities and have adequate space for loading guest molecules. After processing or modification, the starch-containing channel structures can be used for food and drug encapsulation and delivery. This article reviews the formation and determination of starch internal channels, and the influence of different factors (such as starch species and processing conditions) on the channel structure. It also discusses relevant starch preparation methods (physical, chemical, enzymatic, and synergistic), and the encapsulation effect of starch containing internal channels on different substances. In addition, the role of internal channels in regulating the starch digestion rate and other aspects is also discussed here. This review highlights the significant multifunctional applications of starch with a channel structure

Preparation and characterization of gliadin-based core-shell microcapsules by three antisolvent approaches

Gliadin, a versatile wheat-derived protein, has great potential in the creation of nanostructured delivery systems for encapsulating various hydrophobic bioactive substances. Despite gliadin's well-established potential in creating nanostructured delivery systems for hydrophobic substances, its utilization for encapsulating hydrophilic compounds remains a relatively unexplored domain. This study investigated the feasibility of preparing gliadin-based core-shell microcapsules using different antisolvent methods and assessed their controlled release capabilities for hydrophilic compounds. It employed three commonly used food polysaccharides, alginate, κ-carrageenan, and agar, as hydrophilic microbeads and selected thiamine and ethyl maltol as model compounds. The microcapsules were constructed by two steps: 1) The microbeads were prepared by a water-in-oil emulsion template under different gelling conditions; 2) The microbeads were dispersed into aqueous ethanol/urea/acetic acid gliadin solutions, during which the slow migration of water from inside the microbeads to the outer gliadin solution decreased the solubility of gliadin and promoted the deposition of gliadin onto the surface of the microbeads, finally leading to the formation of the core-shell structure. The resulting core-shell microcapsules exhibited adjustable particle sizes from 80.0 to 850.0 μm in diameter and shell thickness ranging from 8.0 to 30.0 μm. Moreover, the microcapsules exhibited controlled release behavior for hydrophilic compounds, with only 20.0% of thiamine being released after 90 min, and this release rate can be finely tuned by controlling the shell thickness. These gliadin-based core-shell microcapsules are considered as promising carriers for the controlled delivery of hydrophilic compounds

Eupatilin Attenuates Ethanol Withdrawal-Induced Anxiety-like Behavior in Rats by Improving Ventral Hippocampus GABAa Transmission

Objective: To study the improving effect of Eupatilin (Eptl) on ethanol withdrawal (EtOHWI)-induced anxiety-like behavior in rats and probe the mechanisms related to ventral hippocampus (vHippo). Methods: Thirty-two adult male Sprague-Dawley rats were randomly divided into four groups, 8 rats per group: Saline-treated control group, EtOHWI model group, low-dose Eptl treatment group and high-dose Eptl treatment group. The EtOHWI was established by intraperitoneal injection of 3 g/kg of ethanol (20% volume/volume, dissolved in saline) once a day for 28 days followed by 3 days of withdrawal, during the withdrawal period, the low-and the high-dose Eptl treatment groups were respectively given 10 and 30 mg/kg Eptl through oral route once a day, while the saline control group was administered with an equal volume of saline. Thirty minutes after the third Eptl, all the rats were subjected to open filed (OF) and elevated plus maze (EPM) tests to detect anxiety-like behaviors. The serum coritosterone (CORT) concentration and vHippo γ-aminobutyric acid (GABA) secretion were measured by enzyme linked immunosorbent assay (ELISA), and vHippo glutamic acid decarboxylase 67 (GAD 67) mRNA relative expression was assayed by real-time quantitative polymerase chain reaction. The protein expression of GABAa receptor α1 (GABAaRα1), GABAaRα2, nuclear factor E2-related factor 2 (Nrf2), heme oxygense-1 (HO-1) in the vHippo were analyzed by Western blot. The levels of MDA, T-SOD, CAT and GSH, IL-6 and TNF-α were measured by commercial kits. Meanwhile, in the in vitro experiment, the nuclear levels of Nrf2 in HT22 cells were detected via immunofluorescent technique. Results: Compared with the rats in the EtOHWI group, the rats in low and high-dose Eptl treatment groups moving distance increased significantly (P<0.01) in the central region of OF which was 70.62% and 124.21% respectively, and moving time increased significantly (P<0.05 or P<0.01) which was 251.75% and 371.62% respectively in the central zone of the OF. Visited more frequently (P<0.05 or P<0.01) which was 110.33% and 207.32% respectively, and stayed time increased significantly (P<0.05 or P<0.01) which was 99.56% and 184.18% respectively in the open arms of the EPM1. In biochemical assays, compared with those in EtOHWI rats, in the rats of low-dose and high-dose Eptl treatment groups, the serum CORT concentrations decreased significantly (P<0.01). The vHippo GABA and GAD67 mRNA levels increased significantly (P<0.05 or P<0.01). The protein expression of GABAaRα1, GABAaRα2, Nrf2, HO-1 in the vHippo increased significantly (P<0.05 or P<0.01). The level of MDA decreased significantly (P<0.01), while the activities of T-SOD and CAT, as well as the level of GSH increased respectively significantly (P<0.05 or P<0.01). The levels of IL-6 and TNF-α decreased significantly (P<0.05 or P<0.01). In the in vitro experiment, the immunofluorescent assay showed that compared with blank control group, Nrf2 level in nucleus of HT22 stimulated by 200 μmol/L H2O2 increased significantly (P<0.01), whereas pretreatment with 30 μmol/L Eptl inhibited the increase of Nrf2 level (P<0.05). Conclusion: Eptl attenuates EtOHWI-induced anxiety-like behavior in rats, which may be mediated by regulating the vHippo GABAaR transmissional disorder of EtOHWI rats via its antioxidant and anti-inflammatory activities

Identification of macrophage-related genes in sepsis-induced ARDS using bioinformatics and machine learning

Abstract Sepsis-induced acute respiratory distress syndrome (ARDS) is one of the leading causes of death in critically ill patients, and macrophages play very important roles in the pathogenesis and treatment of sepsis-induced ARDS. The aim of this study was to screen macrophage-related biomarkers for the diagnosis and treatment of sepsis-induced ARDS by bioinformatics and machine learning algorithms. A dataset including gene expression profiles of sepsis-induced ARDS patients and healthy controls was downloaded from the gene expression omnibus database. The limma package was used to screen 325 differentially expressed genes, and enrichment analysis suggested enrichment mainly in immune-related pathways and reactive oxygen metabolism pathways. The level of immune cell infiltration was analysed using the ssGSEA method, and then 506 macrophage-related genes were screened using WGCNA; 48 showed differential expression. PPI analysis was also performed. SVM-RFE and random forest map analysis were used to screen 10 genes. Three key genes, SGK1, DYSF and MSRB1, were obtained after validation with external datasets. ROC curves suggested that all three genes had good diagnostic efficacy. The nomogram model consisting of the three genes also had good diagnostic efficacy. This study provides new targets for the early diagnosis of sepsis-induced ARDS

A multiobjective evolutionary algorithm based on decision variable classification for many-objective optimization

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Multiobjective evolutionary algorithms (MOEAs) have faced the challenge of balancing diversity and convergence in dealing with many-objective optimization problems (MaOPs). Most of them use a series of strategies to increase the selection pressure among solutions for convergence promotion, or additional auxiliary strategies for diversity maintenance. Decision variable classification (DVC), as the method that analyzes the feature of an MaOP, can help MOEAs search for optimal solutions in terms of convergence and diversity through optimizing the corresponding category of decision variables. Therefore in this paper, we propose a new DVC method by analyzing the monotonicities of objectives. Unlike other DVC methods, it does not need to consider dominance relationships or help with extra vectors. Based on the classification results, we design a new directional crossover (DC) method for generating promising solutions. This crossover method has a higher probability that the generated offspring can integrate the advantages of the parents in convergence and diversity. Incorporating it with MOEA, a DVC-based MOEA (DVC-MOEA) is proposed for dealing with MaOPs. In DVC-MOEA, two archives focusing on convergence and diversity separately are maintained. In addition, an interval mapping(IM) strategy is designed to obtain solutions with good diversity, especially for some problems with biased features. To evaluate the performance of DVC-MOEA on MaOPs, comparison experiments are conducted on two wide used benchmarks with nine state-of-the-art MOEAs. The experimental results show that DVC-MOEA has high competitiveness over these MOEAs in dealing with MaOPs. Moreover, three variants are compared with DVC-MOEA respectively, and the comparison experimental results confirm the effect of the three strategies (DVC, DC, and IM) in our proposed algorithm