Ultra performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry/mass spectrometry(UPLC-Q-TOF-MS/MS), network pharmacology, and animal experiments were integrated o explore the blood glucose-lowering effects and mechanisms of Poria aqueous extract. Firstly, the active components of Poria aqueous extract were identified by UPLC-Q-TOF-MS/MS. Subsequently, network pharmacology was employed to predict the blood glucose-lowering components and mechanisms of Poria aqueous extract. Finally, a rat model of diabetes mellitus, 16S rDNA sequencing, and Western blot were employed to investigate the blood glucose-lowering effect and mechanism of Poria aqueous extract. A total of 39 triterpenoids were identified in the Poria aqueous extract, among them, 25-hydroxypachymic acid, 25α-hydroxytumulosic acid, 16α-hydroxytrametenolic acid, polyporenic acid C, and tumulosic acid may be the main active ingredients for treating diabetes. The Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis revealed that Poria might exert its therapeutic effects through multiple pathways such as NOD-like receptor signaling pathway, nuclear factor-kappa B(NF-κB) signaling pathway, and tumor necrosis factor(TNF) signaling pathway. The results of animal experiments demonstrated that Poria aqueous extract significantly reduced the levels of blood glucose and lipids and regulated the intestinal flora in diabetic rats. The main affected taxa included g＿Escherichia-Shigella, g＿Corynebacterium, g＿Prevotella＿9, g＿Prevotellaceae＿UCG-001, and g＿Bacteroidota＿unclassified. In addition, Poria aqueous extract lowered the levels of D-lactic acid and lipopolysaccharide, alleviated colonic mucosal damage, significantly down-regulated the protein levels of NOD-like receptor pyrin domain-containing protein 3(NLRP3), NF-κB, and TNF-α, and significantly up-regulated the protein levels of zonula occludens 1 and occludin in diabetic rates. Poria aqueous extract may play a role in treating diabetes mellitus by repairing the intestinal flora disturbance, protecting the intestinal barrier function, and inhibiting the NF-κB/NLRP3 signaling pathway. The results provide a scientific basis for clinical application and expansion of indications of Poria.
Animals ; Rats ; Network Pharmacology ; Tandem Mass Spectrometry ; Male ; Drugs, Chinese Herbal/pharmacology* ; Chromatography, High Pressure Liquid ; Blood Glucose/drug effects* ; Rats, Sprague-Dawley ; Hypoglycemic Agents/administration & dosage* ; Poria/chemistry* ; Diabetes Mellitus, Experimental/metabolism* ; NF-kappa B/genetics* ; Gastrointestinal Microbiome/drug effects* ; Humans

Objective: To explore the association between genetic variants of matrix metalloproteinase enzyme 2 (MMP2) gene and the blood pressure of children and adolescents. Methods: This cross-sectional study was performed in 2016 and included 4 155 children and adolescents in the urban area of Guangzhou. Physical examinations (including body height, weight, and blood pressure), questionnaires (including general characteristics, physical exercise, parental educational level, household income, etc.), and blood sampling were performed. Multivariable linear regression models were used to investigate the associations of MMP2 genetic variations (rs243865, rs7201) and the genetic risk score (GRS) level with standardized blood pressure. Mediating effect of standardized body mass index (BMI) was further assessed by process analysis in the association between GRS level and blood pressure, and potential additive interaction between physical activity and GRS level was analyzed using the product term in the regression model. Results: A total of 4 155 primary and secondary schoolchildren were finally included in the analysis, consisting of 1 401 (33.7%) second grade pupils of primary school, 1 422 (34.2%) first grade pupils of middle school, and 1 332 (32.1%) first-grade students of senior high school. After adjusting for age, sex, parental educational level, and family income, as compared to the rs243865 TT genotype, the CC/CT genotype increased diastolic blood pressure (DBP) by 0.461 standard deviations (SD) (β for dominant model=0.461, 95%CI 0.199-0.723). When compared to the rs7201 CC genotype, the AA/AC genotype showed 0.147 SD higher systolic blood pressure (SBP) (β for recessive model=0.147, 95%CI 0.014-0.279) and 0.171 SD increased DBP (β for recessive model=0.171, 95%CI 0.039-0.304). For each increment of GRS level, SBP and DBP increased by 0.151 SD (β for dominant model=0.151, 95%CI 0.029-0.272) and 0.242 SD (β=0.242, 95%CI 0.120-0.363), respectively. The mediating effect of BMI accounted for 28.3% and 12.6% of the total effect of GRS on SBP and DBP, respectively. After controlling BMI, the direct effect of GRS on DBP remained statistically significant (P<0.001). The insufficient moderate-to-vigorous physical activity (<0.5 h/d) showed a significant interaction with GRS on SBP under additive scale (β for interaction=0.518, 95%CI 0.088-0.949, P=0.018). Conclusions: rs243865 and rs7201 variants in MMP2 gene are associated with the elevated blood pressure of children and adolescents. Obesity may yield a mediation role in the associations, while insufficient physical activity may have a positively additive interaction with MMP2 genetic variants.
Adolescent ; Child ; Humans ; Blood Pressure/genetics* ; Body Mass Index ; Cross-Sectional Studies ; Hypertension/genetics* ; Matrix Metalloproteinase 2/genetics* ; Pediatric Obesity/genetics* ; Exercise/genetics*

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.
Blood Pressure ; GTP-Binding Proteins ; Gastrointestinal Microbiome ; Humans ; Hypertension/genetics* ; Receptors, G-Protein-Coupled/metabolism*

Objective Angiotensin Ⅱ (Ang Ⅱ)-induced vascular damage is a major risk of hypertension. However, the underlying molecular mechanism of AngⅡ-induced vascular damage is still unclear. In this study, we explored the novel mechanism associated with Ang II-induced hypertension. Methods We treated 8- to 12-week-old C57BL/6J male mice with saline and Ang Ⅱ(0.72 mg/kg·d) for 28 days, respectively. Then the RNA of the media from the collected mice aortas was extracted for transcriptome sequencing. Principal component analysis was applied to show a clear separation of different samples and the distribution of differentially expressed genes was manifested by Volcano plot. Functional annotations including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to reveal the molecular mechanism of Ang Ⅱ-induced hypertension. Finally, the differentially expressed genes were validated by using quantitative real-time PCR. Results The result revealed that a total of 773 genes, including 599 up-regulated genes and 174 down-regulated genes, were differentially expressed in the aorta of Ang Ⅱ-induced hypertension mice model. Functional analysis of differentially expressed genes manifested that various cellular processes may be involved in the Ang Ⅱ-induced hypertension, including some pathways associated with hypertension such as extracellular matrix, inflammation and immune response. Interestingly, we also found that the differentially expressed genes were enriched in vascular aging pathway, and further validated that the expression levels of insulin-like growth factor 1 and adiponectin were significantly increased (P<0.05). Conclusion We identify that vascular aging is involved in Ang Ⅱ-induced hypertension, and insulin-like growth factor 1 and adiponectin may be important candidate genes leading to vascular aging.
Aging ; Angiotensin II ; Animals ; Aorta/physiopathology* ; Blood Pressure/genetics* ; Gene Expression Profiling/methods* ; Gene Ontology ; Hypertension/genetics* ; Male ; Mice, Inbred C57BL ; Reverse Transcriptase Polymerase Chain Reaction

OBJECTIVE: To explore the diagnostic value of the serum metabolites identified by high-performance liquid chromatography-mass spectrometry (HPLC/MS) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: A total of 126 patients admitted to Tianjin Third Central Hospital were enrolled, including 27 patients with HBV-related hepatitis with negative viral DNA (DNA-N), 24 with HBV-related hepatitis with positive viral DNA, 24 with HBV-related liver cirrhosis, 27 with HBV-related HCC undergoing surgeries or radiofrequency ablation, and 24 with HBV-related HCC receiving interventional therapy, with 25 healthy volunteers as the normal control group. Serum samples were collected from all the subjects for HPLC/MS analysis, and the data were pretreated to establish an orthogonal partial least- squares discriminant analysis (OPLS-DA) model. The differential serum metabolites were preliminarily screened by comparisons between the HBV groups and the control group, and the characteristic metabolites were identified according to the results of non-parametric test. The potential clinical values of these characteristic metabolites were evaluated using receiver operator characteristic curve (ROC) analysis. RESULTS: A total of 25 characteristic metabolites were identified in the HBV- infected patients, including 9 lysophosphatidylcholines, 2 fatty acids, 17α-estradiol, sphinganine, 5-methylcytidine, vitamin K2, lysophosphatidic acid, glycocholic acid and 8 metabolites with few reports. The patients with HBV- related HCC showed 22 differential serum metabolites compared with the control group, 4 differential metabolites compared with patients with HBV-related liver cirrhosis; 10 differential metabolites were identified in patients with HBV-related HCC receiving interventional therapy compared with those receiving surgical resection or radiofrequency ablation. From the normal control group to HBV-related HCC treated by interventional therapy, many metabolites underwent variations following a similar pattern. CONCLUSIONS We identified 25 characteristic metabolites in patients with HBV-related HCC, and these metabolites may have potential clinical values in the diagnosis of HBV-related HCC. The continuous change of some of these metabolites may indicate the possibility of tumorigenesis, and some may also have indications for the choice of surgical approach.
Carcinoma, Hepatocellular ; blood ; diagnosis ; virology ; Case-Control Studies ; Chromatography, High Pressure Liquid ; DNA, Viral ; blood ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; blood ; virology ; Humans ; Liver Cirrhosis ; virology ; Liver Neoplasms ; blood ; diagnosis ; virology ; Mass Spectrometry ; Metabolome ; Metabolomics ; ROC Curve

Stroke is a complex disease and one of the main causes of morbidity and mortality among the adult population. A huge variety of factors is known to influence patient outcome, including demographic variables, comorbidities or genetics. In this review, we expound what is known about the influence of clinical variables and related genetic risk factors on ischemic stroke outcome, focusing on acute and subacute outcome (within 24 to 48 hours after stroke and until day 10, respectively), as they are the first indicators of stroke damage. We searched the PubMed data base for articles that investigated the interaction between clinical variables or genetic factors and acute or subacute stroke outcome. A total of 61 studies were finally included in this review. Regarding the data collected, the variables consistently associated with acute stroke outcome are: glucose levels, blood pressure, presence of atrial fibrillation, prior statin treatment, stroke severity, type of acute treatment performed, severe neurological complications, leukocyte levels, and genetic risk factors. Further research and international efforts are required in this field, which should include genome-wide association studies.
Adult ; Atrial Fibrillation ; Blood Pressure ; Comorbidity ; Genetics ; Genome-Wide Association Study ; Glucose ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Leukocytes ; Mortality ; Risk Factors ; Stroke

BACKGROUND/OBJECTIVES: Glutathione s-transferase (GST) is involved in the formation of a multigene family comprising phase II detoxification enzymes, involved in the detoxification of reactive oxygen species. This study evaluated whether daily supplementation with kale juice could modulate levels of plasma antioxidant vitamins and oxidative stress-related parameters. We further examined whether this modulation was affected by combined GSTM1 and T1 polymorphisms. SUBJECTS/METHODS: Totally, 84 subclinical hypertensive patients having systolic blood pressure (BP) over 130 mmHg or diastolic BP over 85 mmHg, received 300 mL of kale juice daily for 6 weeks. Blood samples were drawn before start of study and after completion of 6 weeks. RESULTS: After supplementation, we observed significant decrease in DNA damage and increase in erythrocyte catalase activity in all genotypes. Plasma level of vitamin C was significantly increased in the wild/null and double null genotypes. The plasma levels of β-carotene, erythrocyte glutathione peroxidase activity, and nitric oxide were increased only in the wild/null genotype after kale juice supplementation. CONCLUSIONS: The effect of kale juice was significantly greater in the GSTM1 null genotype and wild/null genotype groups, suggesting possibility of personalized nutritional prescriptions based on personal genetics.
Ascorbic Acid ; Blood Pressure ; Brassica* ; Catalase ; DNA Damage ; Erythrocytes ; Genetics ; Genotype ; Glutathione Peroxidase ; Glutathione Transferase* ; Glutathione* ; Humans ; Hypertension ; Metabolic Detoxication, Phase II ; Multigene Family ; Nitric Oxide ; Oxidative Stress ; Plasma ; Prescriptions ; Reactive Oxygen Species ; Vitamins*

The pathophysiology of hypertension, which affects over 1 billion individuals worldwide, involves the integration of the actions of multiple organ systems, including the kidney. The kidney, which governs sodium excretion via several mechanisms including pressure natriuresis and the actions of renal sodium transporters, is central to long term blood pressure regulation and the salt sensitivity of blood pressure. The impact of renal sodium handling and the salt sensitivity of blood pressure in health and hypertension is a critical public health issue owing to the excess of dietary salt consumed globally and the significant percentage of the global population exhibiting salt sensitivity. This review highlights recent advances that have provided new insight into the renal handling of sodium and the salt sensitivity of blood pressure, with a focus on genetic, inflammatory, dietary, sympathetic nervous system and oxidative stress mechanisms that influence renal sodium excretion. Increased understanding of the multiple integrated mechanisms that regulate the renal handling of sodium and the salt sensitivity of blood pressure has the potential to identify novel therapeutic targets and refine dietary guidelines designed to treat and prevent hypertension.
Blood Pressure ; Genetics ; Hypertension ; Inflammation ; Kidney ; Natriuresis ; Nutrition Policy ; Oxidative Stress ; Public Health ; Sodium* ; Sympathetic Nervous System

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.
Antitubercular Agents/blood/*therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Chromatography, High Pressure Liquid ; Drug Monitoring ; Humans ; Nutritional Status ; Pharmacogenetics ; Tandem Mass Spectrometry ; Tuberculosis/*drug therapy

PURPOSE: Although it is well known thatmortality and morbidity due to cardiovascular diseases are higher in salt-sensitive subjects than in salt-resistant subjects, their underlying mechanisms related to obesity remain unclear. Here, we focused on salt-sensitive gene variants unrelated to monogenic obesity that interacted with sodium intake in humans. METHODS: This review was written based on the modified 3(rd) step of Khans' systematic review. Instead of the literature, subject genes were based on candidate genes screened from our preliminary Genome-Wide Association Study (GWAS). Finally, literature related to five genes strongly associated with salt sensitivity were analyzed to elucidate the mechanism of obesity. RESULTS: Salt sensitivity is a measure of how blood pressure responds to salt intake, and people are either salt-sensitive or salt-resistant. Otherwise, dietary sodium restriction may not be beneficial for everyone since salt sensitivity may be associated with inherited susceptibility. According to our previous GWAS studies, 10 candidate genes and 11 single nucleotide polymorphisms (SNPs) associated with salt sensitivity were suggested, including angiotensin converting enzyme (ACE), α-adducin1 (ADD1), angiotensinogen (AGT), cytochrome P450 family 11-subfamily β-2 (CYP11β-2), epithelial sodium channel (ENaC), G-protein b3 subunit (GNB3), G protein-coupled receptor kinases type 4 (GRK4 A142V, GRK4 A486V), 11β-hydroxysteroid dehydrogenase type-2 (HSD 11β-2), neural precursor cell-expressed developmentally down regulated 4 like (NEDD4L), and solute carrier family 12(sodium/chloride transporters)-member 3 (SLC 12A3). We found that polymorphisms of salt-sensitive genes such as ACE, CYP11β-2, GRK4, SLC12A3, and GNB3 may be positively associated with human obesity. CONCLUSION: Despite gender, ethnic, and age differences in genetics studies, hypertensive obese children and adults who are carriers of specific salt-sensitive genes are recommended to reduce their sodium intake. We believe that our findings can contribute to the prevention of early-onset of chronic diseases in obese children by facilitating personalized diet-management of obesity from childhood to adulthood.
Adult ; Angiotensinogen ; Blood Pressure ; Cardiovascular Diseases ; Child ; Chronic Disease ; Cytochrome P-450 Enzyme System ; Epithelial Sodium Channels ; Genetics ; Genome-Wide Association Study ; GTP-Binding Proteins ; Humans ; Hypertension ; Obesity* ; Oxidoreductases ; Peptidyl-Dipeptidase A ; Phosphotransferases ; Polymorphism, Single Nucleotide ; Sodium ; Sodium, Dietary