Prolonged or Transition to Metabolically Unhealthy Status, Regardless of Obesity Status, Is Associated with Higher Risk of Cardiovascular Disease Incidence and Mortality in Koreans.

The risk of chronic disease and mortality may differ by metabolic health and obesity status and its transition. We investigated the risk of cardiovascular disease (CVD) and cancer incidence and mortality according to metabolic health and obesity status and their transition using the nationally representative Korea National Health and Nutrition Examination Survey (KNHANES) and the Ansan-Ansung (ASAS) cohort of the Korean Genome and Epidemiology Study. Participants that agreed to mortality linkage (n = 28,468 in KNHANES and n = 7530 adults in ASAS) were analyzed (mean follow-up: 8.2 and 17.4 years, respectively). Adults with no metabolic risk factors and BMI <25 or ≥25 kg/m2 were categorized as metabolically healthy non-obese (MHN) or metabolically healthy obese (MHO), respectively. Metabolically unhealthy non-obese (MUN) and metabolically unhealthy obese (MUO) adults had ≥1 metabolic risk factor and a BMI < or ≥25 kg/m2, respectively. In KNHANES participants, MUN, and MUO had higher risks for cardiovascular mortality, but not cancer mortality, compared with MHN adults. MHO had 47% and 35% lower risks of cancer mortality and all-cause mortality, respectively, compared to MHN. Similar results were observed in the ASAS participants. Compared to those persistently MHN, the risk of CVD was greater when continuously MUN or MUO. Transitioning from a metabolically healthy state to MUO also increased the risk of CVD. Few associations were found for cancer incidence. Using a nationally representative cohort and an 18-year follow-up cohort, we observed that the risk of CVD incidence and mortality and all-cause mortality, but not cancer incidence or mortality, increases with a continuous or a transition to an unhealthy metabolic status in Koreans.

Long-term outcomes of transforaminal epidural steroid injection in patients with lumbosacral radicular pain according to the location, type, and size of herniated lumbar disc.

OBJECTIVES: Transforaminal epidural steroid injection (TFESI) is widely used to manage lumbosacral radicular pain due to herniated lumbar disc (HLD). OBJECTIVES: We evaluated the long-term outcomes of TFESI in patients with lumbosacral radicular pain due to an HLD by the location, type, and size of the HLD. METHODS: In total, 114 patients who received the initial TFESI at least 4 years ago completed a telephone interview. We investigated the presence of radicular pain, degree of current pain, current pain medications and TFESIs, additional TFESIs, progression to surgery, and trouble in performing daily life activities and occupational job duties. We classified the included patients by the location, type, and size of the HLD, and evaluated whether these factors affected the long-term outcomes of TFESI. RESULTS: At least 4 years after the initial TFESI, radicular pain was completely resolved in 45% of the patients. However, 30% patients were on oral painkillers or repetitive TFESIs or had undergone surgery and 15% had difficulty in performing daily life activities and occupational job duties. A larger number of patients with extruded lumbar disc herniation required additional TFESIs than those with protruded lumbar disc herniation. Apart from this, the outcomes did not significantly differ by the location, type, and size of the HLD. CONCLUSIONS: Our findings provide useful information to clinicians managing radicular pain due to HLD.

Adiposity and mortality in Korean adults: a population-based prospective cohort study.

BACKGROUND: The Asia-Pacific obesity classification recommends using lower BMI cutoffs in Asians compared with those in Western populations. However, the supporting evidence is scarce and little is known about the exact shape of the relations between adiposity and mortality in Asians. OBJECTIVES: We investigated the relations of BMI (in kg/m2), waist circumference, and predicted body fat mass with mortality using a population-based prospective cohort of Korean men and women. METHODS: This analysis included 44,060 Korea National Health and Nutrition Examination Survey 2007-2014 participants who agreed to mortality follow-up through 31 December, 2016. At baseline, height, weight, and waist circumference were measured. Using DXA data, we derived predicted body fat and fat-free mass. Cox proportional hazards models were used to estimate HRs and 95% CIs for the associations with mortality, adjusting for potential confounders. We tested for nonlinearity using the likelihood ratio test comparing nonlinear restricted cubic spline models with linear models. RESULTS: During ≤9.5 y of follow-up, 1682 deaths were identified. The relations of BMI with all-cause and cardiovascular mortality were J-shaped with the nadir at BMI = 25.0-29.9 (P-nonlinearity < 0.001). Among participants without a history of cancer or cardiovascular disease, waist circumference (≥95 compared with 75.0-79.9 cm: HR: 2.10; 95% CI: 1.54, 2.86) and predicted body fat mass (highest compared with lowest sextiles: 2.55; 95% CI: 1.60, 4.06) were positively associated with all-cause mortality (all P-nonlinearity ≤ 0.03), as well as cancer and cardiovascular mortality. The highest mortality was observed among participants who had both high predicted fat mass and low fat-free mass. CONCLUSIONS: Our data suggest a strong positive association between adiposity and mortality in a population without pre-existing disease. We observed the lowest mortality at BMI = 25.0-29.9, suggesting that the current cutoff for overweight (BMI ≥23) may require re-evaluation and that BMI alone may not be a useful measure for indicating adiposity in Asians.

Glyoxal and Methylglyoxal as E-cigarette Vapor Ingredients-Induced Pro-Inflammatory Cytokine and Mucins Expression in Human Nasal Epithelial Cells.

BACKGROUND: Glyoxal (GO), and methylglyoxal (MGO) are among the most toxic compounds emitted by electronic cigarette (E-cig) and regular tobacco cigarette smoke. Airway diseases presented mucus over production as their major pathophysiologic feature. However, the effects of GO and MGO on pro-inflammatory cytokines and mucin expression in human nasal epithelial cells, as well as the underlying signaling pathway, have not yet been studied. OBJECTIVE: This study is to determine whether GO and MGO induce pro-inflammatory cytokines, and MUC5AC/5B expression via mitogen-activated protein kinase (MAPK)s and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. METHODS: The effect of GO, and MGO on pro-inflammatory cytokines, mucins expression and the signalling pathway of GO and MGO were investigated using water-soluble tetrazolium salt-1, enzyme immunoassays, and immunoblot analysis with specific inhibitors and small interfering RNA. RESULTS: GO and MGO did not affect cell viability up to 2 mM in human nasal epithelial cells. GO and MGO increased production of pro-inflammatory such as interleukin (IL)-1ß and IL-6) and MUC5AC/5B. Additionally, GO and MGO significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and NF-κB. Whether ERK1/2, p38 MAPK, and NF-κB signaling pathway were involved in GO and MGO-induced production of pro-inflammatory cytokines (IL-1ß and IL-6) and MUC5AC/5B, we used specific inhibitors and siRNA transfection. These significantly repressed GO- and MGO-induced expression of pro-inflammatory cytokines (IL-1ß and IL-6) and MUC5AC/5B. CONCLUSIONS: GO and MGO induced pro-inflammatory cytokines and MUC5AC/5B expression via ERK1/2, p38 MAPK, and NF-κB in human nasal epithelial cells. These results suggested that GO and MGO may be involved in mucus hypersecretion-related airway diseases.

Effect of chitinase-3-like protein 1 on glucose metabolism: In vitro skeletal muscle and human genetic association study.

We investigated the effect of chitinase-3-like protein 1 (CHI3L1) on glucose metabolism and its underlying mechanisms in skeletal muscle cells, and evaluated whether the observed effects are relevant in humans. CHI3L1 was associated with increased glucose uptake in skeletal muscles in an AMP-activated protein kinase (AMPK)-dependent manner, and with increased intracellular calcium levels via PAR2. The improvement in glucose metabolism observed in an intraperitoneal glucose tolerance test on male C57BL/6J mice supported this association. Inhibition of the CaMKK was associated with suppression of CHI3L1-mediated glucose uptake. Additionally, CHI3L1 was found to influence glucose uptake through the PI3K/AKT pathway. Results suggested that CHI3L1 stimulated the phosphorylation of AS160 and p38 MAPK downstream of AMPK and AKT, and the resultant GLUT4 translocation. In primary myoblast cells, stimulation of AMPK and AKT was observed in response to CHI3L1, underscoring the biological relevance of CHI3L1. CHI3L1 levels were elevated in cells under conditions that mimic exercise in vitro and in exercised mice in vivo, indicating that CHI3L1 is secreted during muscle contraction. Finally, similar associations between CHI3L1 and metabolic parameters were observed in humans alongside genotype associations between CHI3L1 and diabetes at the population level. CHI3L1 may be a potential therapeutic target for the treatment of diabetes.

Compression of the Lateral Antebrachial Cutaneous Nerve due to Leakage of Iron after an Intravenous Iron Infusion.

Skin staining due to iron leakage into the subcutaneous tissue can sometimes occur during intravenous iron infusion. We describe a case of lateral antebrachial cutaneous nerve (LACN) entrapment due to extravasated iron after an intravenous iron infusion. A 41-year-old woman received an intravenous ferric carboxymaltose infusion for iron deficiency anemia. However, during the infusion, extravasation of iron occurred and brown pigmentation developed on the lateral side of the cubital fossa. Sixteen months later, the patient still had some staining in her anterolateral elbow and proximal forearm. In addition, she complained of tingling pain over her left forearm. Ultrasonography (US) revealed a lateral antebrachial cutaneous nerve (LACN) under the stained area. When we swept the stained area with the US transducer, she reported a tingling pain on her left lateral forearm, the region innervated by the left LACN. Therefore, we considered that the pain resulted from the compression of the left LACN by the leaked iron during the intravenous infusion. Leaked iron can compress the cutaneous nerve and result in neuropathic pain and cosmetic problems. When patients with skin staining after iron infusion have neuropathic pain, clinicians should consider the possibility of entrapment of the cutaneous nerves.

Smoking May Affect Pulmonary Function through DNA Methylation: an Epigenome-Wide Association Study in Korean Men.

Smoking is a risk factor for various disease outcomes and is one of the modifiers of DNA methylation. We aimed to identify smoking-related DNA methylation sites (CpG-sites) and test whether one identified CpG-site is associated with smoking-related traits and pulmonary function. We obtained DNA methylation data of 209 men from the Korean Genome and Epidemiology Study analyzed by Illumina's HumanMethylation450 array. To identify smoking-related DNA methylation sites, epigenome-wide association analysis of smoking status was conducted, adjusting for age, area, current drinking status, and body mass index. We assessed the association between smoking intensity and DNA methylation of cg05951221 (AHRR), the CpG showing the strongest largest difference in DNA methylation among the 5 hypomethylated CpGs in current smokers compared to never smokers. The association between DNA methylation and pulmonary function was examined longitudinally resulting in a positive association between DNA methylation and forced expiratory volume in 1 second/forced vital capacity, regardless of adjustment for smoking status. This suggests that DNA methylation associates with long-term pulmonary function. Our study contributes to explaining the relationship between smoking and pulmonary function via DNA methylation.

ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by ß-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

Association between Genetic Variant of Apolipoprotein C3 and Incident Hypertension Stratified by Obesity and Physical Activity in Korea.

Apolipoprotein C3 (APOC3) is an important regulator of lipoprotein metabolism, and has been shown to be strongly associated with hypertriglyceridemia. We tested whether triglyceride-influencing genetic variants at APOC3 (T-455C, C-482T, C1100T, and SstI) are associated with the onset of hypertension (HTN) among Korean adults stratified by lifestyle-related factors in the Ansung⁻Ansan cohort within the Korean Genome and Epidemiology Study. After excluding participants with preexisting cancer, cardiovascular diseases, diabetes, and HTN, a total of 5239 men and women were included at baseline (2001⁻2002), and followed up for a median of 9.8 years. Carriers of the C allele of C1100T with body mass index <25 kg/m² showed a significantly lower HTN risk (hazard ratio (HR) than non-carriers: 0.87, 95% confidence interval (CI): 0.77⁻0.98) after adjusting for covariates. In addition, carriers of the C allele of T-455C and the T allele of C-482T with low physical activity had lower incident HTN than non-carriers (HR: 1.14, 95% CI: 1.03⁻1.26; HR: 1.13, 95% CI: 1.02⁻1.25). Our results suggest that genotype effects in APOC3 on HTN risk have been shown in lean carriers of the C allele of C1100T and in less active people having the C allele of T-455C and T allele of C-482T in a large sample of the Korean population.

Association among genetic variants in the vitamin D pathway and circulating 25-hydroxyvitamin D levels in Korean adults: results from the Korea National Health and Nutrition Examination Survey 2011-2012.

Vitamin D deficiency affects >60% of the Korean population. Recent reports in Caucasian, African American, and Chinese populations indicate an association between vitamin D status and related single nucleotide polymorphisms (SNPs), but specific associations differ among study populations. We investigated the relationship between five SNPs involved in the vitamin D metabolic pathway (DHCR7 rs12785878, GC rs2282679, CYP2R1 rs12794714, CYP2R1 rs10741657, and CYP24A1 rs6013897) and serum 25-hydroxyvitamin D [25(OH)D] status in Koreans using the Korea National Health and Nutrition Examination Survey, a nationwide database. Whether the association was modified by demographic and lifestyle factors, including sex, body mass index (BMI), smoking status, drinking status, physical activity, and sun exposure, were also investigated. The results showed the serum level of 25(OH)D was associated with rs12785878, rs2282679, and rs12794714 genotypes, but not with rs10741657 or rs6013897. The genetic risk score (GRS) calculated by summing the number of alleles of these 5 SNPs was associated with low circulating levels of 25(OH)D. However, the negative association between 25(OH)D and GRS was modified by obesity and sun exposure. Specifically, negative associations between 25(OH)D and GRS were present in adults with lower BMI (<25 kg/m2) and longer sun exposure time (≥2 h/day). In conclusion, common variants of vitamin D-related SNPs are associated with vitamin D status in Koreans, and this genetic effect was masked when BMI ≥25 kg/m2 or sun exposure <2 h/day. Additionally, seasonal variation must be considered in future studies among Koreans.

Serum metabolite profile associated with incident type 2 diabetes in Koreans: findings from the Korean Genome and Epidemiology Study.

The identification of metabolic alterations in type 2 diabetes (T2D) is useful for elucidating the pathophysiology of the disease and in classifying high-risk individuals. In this study, we prospectively examined the associations between serum metabolites and T2D risk in a Korean community-based cohort (the Ansan-Ansung cohort). Data were obtained from 1,939 participants with available metabolic profiles and without diabetes, cardiovascular disease, or cancer at baseline. The acylcarnitine, amino acid, amine, and phospholipid levels in fasting serum samples were analyzed by targeted metabolomics. During the 8-year follow-up period, we identified 282 cases of incident T2D. Of all metabolites measured, 22 were significantly associated with T2D risk. Specifically, serum levels of alanine, arginine, isoleucine, proline, tyrosine, valine, hexose and five phosphatidylcholine diacyls were positively associated with T2D risk, whereas lyso-phosphatidylcholine acyl C17:0 and C18:2 and other glycerophospholipids were negatively associated with T2D risk. The associated metabolites were further correlated with T2D-relevant risk factors such as insulin resistance and triglyceride indices. In addition, a healthier diet (as measured by the modified recommended food score) was independently associated with T2D risk. Alterations of metabolites such as amino acids and choline-containing phospholipids appear to be associated with T2D risk in Korean adults.

Resistin upregulates MUC5AC/B mucin gene expression in human airway epithelial cells.

Adipokines, a group of proteins including leptin, visfatin, resistin, and adiponectin, are produced by adipocytes. Among adipokines, resistin is implicated in insulin resistance and inflammatory response modulation. Mucus hypersecretion has been greatly linked to airway diseases, such as asthma, chronic obstructive pulmonary disease, and rhinosinusitis. Increasing evidence has indicated that adipokines, such as leptin and visfatin, play important regulatory roles in various biological processes involved in mucus secretion. However, the effects of resistin on mucin expression in human airway epithelial cells, as well as the underlying mechanisms, have not been investigated yet. We showed that resistin affected mucin expression in human airway epithelial cells via the mitogen-activated protein kinase/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Resistin increased MUC5AC and MUC5B expression in NCI-H292 and primary human nasal epithelial cells. Additionally, it significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and NF-κB. ERK1/2 and p38 specific inhibitors significantly attenuated resistin-induced MUC5AC/5B expression; however, NF-κB inhibitor reduced resistin-induced MUC5AC, but not MUC5B, expression. Knockdown of ERK1, ERK2, and p38 by ERK1, ERK2, and p38 small interfering RNA (siRNA), respectively, significantly blocked resistin-induced MUC5AC and MUC5B mRNA expression. In addition, NF-κB siRNA attenuated resistin-induced MUC5AC, but not MUC5B, expression. These results suggested that resistin induced MUC5AC and MUC5B expression via activation of different signaling pathways in human airway epithelial cells.

Selected Food Consumption Mediates the Association between Education Level and Metabolic Syndrome in Korean Adults.

BACKGROUND/AIMS: Low socioeconomic status (SES) is linked to higher incidence/mortality of cardiovascular disease, but emerging evidence inconsistently reported that education level, a proxy for SES, is related to cardiovascular risk and metabolic syndrome (MetS) in Koreans. Furthermore, limited information is available on whether dietary components would mediate the relationship between education level and cardiovascular risk. We hypothesized that selected food consumption mediates the association between education level and MetS prevalence. METHODS: Data from the Korea National Health and Nutritional Examination Survey (2008-2011) were included in cross-sectional analyses (n = 11,029, 30-64 years). The possible mediating effect of selected food groups (fruits, raw vegetables, red meat, milk, and soft drinks) on the association between education level and MetS was tested using a multiple mediation model. RESULTS: Education level was negatively associated with MetS prevalence. The association between lower education level and higher MetS prevalence was partially mediated by selected food consumption (lower intakes of fruit, red meat and milk; higher intakes of vegetable and soft drink) after adjusted for covariates. Gender also modified the association between education level and MetS prevalence that was more prominent in women than in men. CONCLUSIONS: Selected food consumption substantially contributes to the association between education level and MetS in Korean adults, especially among women.

Trimeric PEG-Conjugated Exendin-4 for the Treatment of Sepsis.

Exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist that regulates blood glucose levels, has been used in the management of type-2 diabetes mellitus. EX4 can be PEGylated to improve its antidiabetic effects by enhancing its stability and extending the circulation half-life. Here, to determine whether PEGylated EX4 is effective for the treatment of sepsis, C-terminal thiol-specific PEGylated EX4s with linear maleimide-PEG-2K, -5K, -20K and trimeric maleimide-PEG-50K (hereafter referred to as EX4-2K, EX4-5K, EX4-20K, and EX4-50K, respectively) were prepared, and their antiseptic responses were investigated. These PEGylated EX4s reduced cecal ligation and puncture (CLP)-induced organ injury by decreasing hyperpermeability, and suppressing interactions between leukocytes and endothelial cells. The binding avidity and stability of EX4-50K toward GLP-1R were superior to that of wild-type EX4, as was the circulation half-life of EX4-50K. In addition, the antiseptic effects of EX4-50K were superior to those of other PEGylated EX4s, which may be attributed to enhanced proteolytic stability, longer circulation half-life, and higher receptor-binding affinity of EX4-50K due to its trimeric PEG structure. Therefore, EX4-50K may decrease CLP-induced septic mortality in vivo. There are currently neither effective preventatives against nor treatment options for sepsis; our results show that EX4-50K has the potential to treat sepsis.

Antitcoagulant and antiplatelet activities of scolymoside.

Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain. Here, the anticoagulant effects of scolymoside, an active compound in C. subternata, were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of scolymoside on plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) expression were evaluated in tumor necrosis factor (TNF)-α-activated human endothelial cells. Treatment with scolymoside resulted in prolonged aPTT and PT and the inhibition of thrombin and FXa activities and production. In addition, scolymoside inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. Scolymoside also elicited anticoagulant effects in mice, including a significant reduction in the PAI-1 to t-PA ratio. Collectively, these findings indicate that scolymoside possesses anticoagulant activities and could be developed as a novel anticoagulant.

Inhibitory effect of exendin-4 on secretory group IIA phospholipase A2.

Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, has been reported to attenuate myocardial ischemia and reperfusion injury and inflammatory or oxidative responses. The expression level of secretory group IIA phospholipase A2 (sPLA2-IIA) is elevated in inflammatory diseases. Lipopolysaccharide (LPS) upregulates the expression of sPLA2-IIA in human umbilical vein endothelial cells (HUVECs). Here, EX4 was examined for its effects on the expression and activity of sPLA2-IIA in HUVECs and mice. Pre-treatment of cells or mice with EX4 inhibited LPS-induced sPLA2-IIA expression and activity. Additionally, EX4 suppressed LPS-induced activation of cytosolic phospholipase A2 (cPLA2) and extracellular signal-regulated kinase (ERK) 1/2. Therefore, these results show that EX4 inhibited LPS-induced expression of sPLA2-IIA by suppressing cPLA2 and ERK 1/2.

Aspalathin and nothofagin from rooibos (Aspalathus linearis) inhibit endothelial protein C receptor shedding in vitro and in vivo.

Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos, which have been reported for their anti-oxidant activity. Increasing evidence has demonstrated that beyond its role in the activation of protein C, endothelial cell protein C receptor (EPCR) is also involved in vascular inflammation. EPCR activity is markedly changed by ectodomain cleavage and its release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of Asp and Not on EPCR shedding. Our results demonstrated that Asp and Not induced potent inhibition of phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1ß, and cecal ligation and puncture (CLP)-induced EPCR shedding. Asp and Not also inhibited the expression and activity of PMA-induced TACE in endothelial cells. Asp and Not also suppressed CLP-induced protein C decrease in mice and thrombin generation in HUVECs. In addition, treatment with Asp and Not resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of Asp and Not as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.

Vascular barrier protective effects of baicalin, baicalein and wogonin in vitro and in vivo.

Inhibition of high mobility group box 1 (HMGB1) protein and restoration of endothelial integrity is emerging as an attractive therapeutic strategy in the management of sepsis. Here, three structurally related polyphenols found in the Chinese herb Huang Qui, baicalin (BCL), baicalein (BCN), and wogonin (WGN), were examined for their effects on lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. According to our data, BCL, BCN, and WGN inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. BCL, BCN, and WGN also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with BCL, BCN, and WGN reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that BCL, BCN, and WGN could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway.

Hyperoside inhibits high-glucose-induced vascular inflammation in vitro and in vivo.

Hyperoside, an active compound from the genera of Hypericum and Crataegus, was reported to have antioxidant, antihyperglycemic, anticancer, anti-inflammatory, and anticoagulant activities. Vascular inflammatory process has been suggested to play a key role in initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, in this study, we attempted to determine whether hyperoside can suppress vascular inflammatory processes induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. Data showed that HG induced markedly increased vascular permeability, monocyte adhesion, expressions of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS), and activation of nuclear factor (NF)-κB. Remarkably, all of the above-mentioned vascular inflammatory effects of HG were attenuated by pretreatment with hyperoside. Vascular inflammatory responses induced by HG are critical events underlying development of various diabetic complications; therefore, our results suggest that hyperoside may have significant therapeutic benefits against diabetic complications and atherosclerosis.

Antiplatelet, anticoagulant, and profibrinolytic activities of cudratricusxanthone A.

Cudratricusxanthone A (CTXA), a natural bioactive compound extracted from the roots of Cudrania tricuspidata Bureau, is known to possess hepatoprotective, antiproliferative and anti-inflammatory activities. However, antiplatelet, anticoagulant, and profibrinolytic properties have not been studied. The anticoagulant activities of CTXA were measured by monitoring activated partial thromboplastin-time (aPTT), prothrombin time (PT), and the activities of cell-based thrombin and activated factor X (FXa). The effects of CTXA on the expressions of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were also tested in tumor necrosis factor-α (TNF-α) activated human umbilical vein endothelial cells. Our data showed that CTXA inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation, prolonged aPTT and PT significantly and inhibited the activities and production of thrombin and FXa. CTXA prolonged in vivo bleeding time and inhibited TNF-α induced PAI-1 production. Furthermore, PAI-1/t-PA ratio was significantly decreased by CTXA. Collectively, these results indicate that CTXA possesses antithrombotic activities and suggest that the current study could provide bases for the development of new anticoagulant agents.