Prevalence and clinical correlates of hyperhomocysteinemia in Chinese urban population with hypertension.

Context: The coexistence of hypertension and elevated homocysteine (Hcy) levels has a mutually reinforcing impact on the susceptibility to cardio-cerebrovascular disease. Objective: The aim was to assess the prevalence, clinical correlation, and demographic characteristics of hyperhomocysteinemia (HHcy) within the Chinese urban population with hypertension. Methods: A cohort of 473 individuals with hypertension were selected from four communities in Shenzhen, China. Demographic attributes, clinical profiles, and lifestyle behaviors were gathered and compared between individuals with and without HHcy. A logistic regression model was employed to examine potential factors associated with the prevalence of HHcy. Correlation between Hcy levels and clinical characteristics was assessed through multiple linear regression analysis. Results: The prevalence of HHcy in the population with hypertension was 31.3%. In comparison to individuals without HHcy, those with HHcy exhibited a higher proportion of males, a higher prevalence of smoking and alcohol consumption, and a higher proportion of cases with the homozygous (TT) genotype at the MTHFR C677T polymorphism. Moreover, individuals with HHcy had lower levels of folic acid (FA), and lower fruit and vitamin B12 intake. Furthermore, the risk factors for HHcy were male (B = 1.430, OR = 4.179) and MTHFR (TT) (B = 1.086, OR = 2.961). In addition, the multiple linear regression analysis revealed a significant association between Hcy levels and gender (B = -2.784, P = 0.004), MTHFR genotypes (B = 1.410, P = 0.005), and FA levels (B = -0.136, P = 0.030). Conclusion: The high prevalence of HHcy among hypertensive patients in this Chinese urban population underscores the necessity for interventions targeting modifiable risk factors such as dietary choices and lifestyle practices.

Near-Infrared Afterglow ONOO--Triggered Nanoparticles for Real-Time Monitoring and Treatment of Early Ischemic Stroke.

Early detection and drug intervention with the appropriate timing and dosage are the main clinical challenges for ischemic stroke (IS) treatment. The conventional therapeutic agents relay fluorescent signals, which require real-time external light excitation, thereby leading to inevitable autofluorescence and poor tissue penetration. Herein, we report endogenous peroxynitrite (ONOO-)-activated BDP-4/Cur-CL NPs that release NIR afterglow signals (λmax 697 nm) for real-time monitoring of the progression of ischemia reperfusion (I/R) brain injury while releasing curcumin for the safe treatment of IS. The BDP-4/Cur-CL NPs exhibited bright NIR afterglow luminescence (maximum 732-fold increase), superb sensitivity (LOD = 82.67 nM), high energy-transfer efficiency (94.6%), deep tissue penetration (20 mm), outstanding antiapoptosis, and anti-inflammatory effects. The activated NIR afterglow signal obtained in mice with middle cerebral artery occlusion (MCAO) showed three functions: (i) the BDP-4/Cur-CL NPs are rapidly activated by endogenous ONOO-, instantly illuminating the lesion area, distinguishing I/R damage from normal areas, which can be successfully used for endogenous ONOO- detection in the early stage of IS; (ii) real-time reporting of in situ generation and dynamic fluctuations of endogenous ONOO- levels in the lesion area, which is of great value in monitoring the evolutionary mechanisms of IS; and (iii) dynamic monitoring of the release of curcumin drug for safe treatment. Indeed, the released curcumin effectively decreased apoptosis, enhanced survival, alleviated neuroinflammation, reduced brain tissue loss, and improved the cognition of MCAO stroke mice. This work is the first example of afterglow luminescence for early diagnosis, real-time reporting, drug tracing, and treatment for IS.

Advanced oxidation protein products upregulate ABCB1 expression and activity via HDAC2-Foxo3α-mediated signaling in vitro and in vivo.

The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.

Resveratrol Inhibits High Glucose-Induced H9c2 Cardiomyocyte Hypertrophy and Damage via RAGE-Dependent Inhibition of the NF-κB and TGF-ß1/Smad3 Pathways.

Hyperglycaemia is associated with the development of cardiac vascular disease. Resveratrol (RES) is a naturally occurring polyphenolic compound that possesses many biological properties, including anti-inflammatory properties and antioxidation functions. Our study aimed to explore the RES's protective roles on high glucose (HG)-induced H9c2 cells and the underlying mechanisms. Small-molecule inhibitors, western blotting (WB), as well as reverse-transcription PCR (RT-PCR) were employed to investigate the mechanisms underlying HG-induced damage in H9c2 cells. RES (40 µg/mL) treatment significantly alleviated HG-induced cardiac hypertrophy and cardiac dysfunction. RES abated the HG-induced increase in the levels of extracellular matrix (ECM) components and inflammatory cytokines, reducing ECM accumulation and inflammatory responses. Additionally, RES administration prevented HG-induced mitochondrion-mediated cardiac apoptosis of myocardial cells. In terms of mechanisms, we demonstrated that RES ameliorated the HG-induced overexpression of receptor for advanced glycation endproducts (RAGE) and downregulation of NF-κB signalling. Moreover, RES inhibited HG-induced cardiac fibrosis by inhibiting transforming growth factor beta 1 (TGF-ß1)/Smad3-mediated ECM synthesis in cultured H9c2 cardiomyocytes. Further studies revealed that the effects of RES against HG-induced upregulation of NF-κB and TGF-ß1/Smad3 pathways were similar to those of FPS-ZM1, a RAGE inhibitor. Collectively, the results implied that RES might help alleviate HG-induced cardiotoxicity via RAGE-dependent downregulation of the NF-κB and TGF-ß/Smad3 pathways. This study provided evidence that RES can be developed as a promising cardioprotective drug.

Advanced oxidation protein products downregulate CYP1A2 and CYP3A4 expression and activity via the NF-κB-mediated signaling pathway in vitro and in vivo.

Uremic toxin accumulation is one possible reason for alterations in hepatic drug metabolism in patients with chronic kidney disease (CKD). However, the types of uremic toxins and underlying mechanisms are poorly understood. In this study, we report the role of advanced oxidation protein products (AOPPs), a modified protein uremic toxin, in the downregulation of cytochromes P450 1A2 (CYP1A2) and P450 3A4 (CYP3A4) expression levels and activities. We found that AOPP accumulation in plasma in a rat CKD model was associated with decreased protein levels of CYP1A2 and CYP3A4. CYP1A2 and CYP3A4 metabolites (acetaminophen and 6ß-hydroxytestosterone, respectively,) in liver microsomes were also significantly decreased. In human hepatocytes, AOPPs significantly decreased CYP1A2 and CYP3A4 protein levels in a dose- and time-dependent manner and downregulated their activities; however, bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect on these parameters. The effect of AOPPs was associated with upregulation of p-IKKα/ß, p-IκBα, p-NF-κB, and inflammatory cytokines protein levels and increases in p-IKKα/ß/IKKα, p-IκBα/IκBα, and p-NF-κB/NF-κB phosphorylation ratios. Further, NF-kB pathway inhibitors BAY-117082 and PDTC abolished the downregulatory effects of AOPPs. These findings suggest that AOPPs downregulate CYP1A2 and CYP3A4 expression and activities by increasing inflammatory cytokine production and stimulating NF-κB-mediated signaling. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD by influencing metabolic enzymes.

Aldose Reductase Inhibitor Engeletin Suppresses Pelvic Inflammatory Disease by Blocking the Phospholipase C/Protein Kinase C-Dependent/NF-κB and MAPK Cascades.

Pelvic inflammatory disease (PID) is a common inflammation in the upper reproductive tract in women and may cause serious and costly consequences without effective treatment. Engeletin is a flavanonol glycoside and a naturally derived aldose reductase (AR) inhibitor that is widely distributed in vegetables, fruits, and plant-based foods. The present study investigated the anti-PID activity of engeletin in a mucilage-induced rat model of PID and LPS-stimulated RAW 264.7 macrophages. Engeletin significantly reduced inflammation and ameliorated the typical uterine pathological changes in PID rats. Engeletin also inhibited AR-dependent PLC/PKC/NF-κB and MAPK inflammatory pathways, as indicated by the suppression of the phosphorylation levels of PLC, PKC, p38, ERK, and JNK and the nuclear translocation of NF-κB p65. In vitro studies demonstrated that engeletin significantly inhibited inflammatory mediator expression and enhanced the phagocytic ability of LPS-induced RAW 264.7 macrophages. RNA interference of AR prevented the engeletin-induced inhibition of inflammatory mediators. Engeletin also inhibited AR-dependent PLC/PKC/NF-κB and MAPK inflammatory pathways, which was consistent with the in vivo results. These findings support engeletin as a potential agent for prevention or treatment of PID.

AGE receptor 1 silencing enhances advanced oxidative protein product-induced epithelial-to-mesenchymal transition of human kidney proximal tubular epithelial cells via RAGE activation.

Advanced oxidative protein products (AOPPs) are novel uremic toxins whose concentrations continuously increases in patients with chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) of tubular cells is the main mechanism underlying CKD pathogenesis. Studies have shown that AOPPs can induce EMT and promote renal fibrosis. However, the mechanism through which AOPPs induce tubular cell-EMT is poorly understood. In this study, we aimed to clarify the mechanisms underlying AOPP-induced EMT in human kidney proximal tubular (HKC-8) epithelial cells. Small molecule inhibitor, CRISPR-Cas9 knockout technology, siRNA knockdown technology, western blot, and reverse transcription-quantitative polymerase chain reaction were applied to investigate the mechanisms underlying AOPP-induced EMT in HKC-8 cells. AOPP treatment was found to significantly induce EMT, as evidenced by increased α-smooth muscle actin (α-SMA) and decreased E-cadherin levels, and upregulated Wnt1, ß-catenin, Tcf4, and Gsk-3ß expression. Conversely, blockade of Wnt/ß-catenin signaling using small molecule inhibitor ICG-001 hindered AOPP-induced EMT. Moreover, knockout of receptor of advanced glycation end-products (RAGE) reversed these aforementioned effects, whereas AGE receptor 1 (AGER1)-specific siRNA transfection enhanced them. Taken together, these data suggested that AOPPs could induce HKC-8 cell EMT by activating the RAGE/Wnt/ß-catenin signaling pathway and AGER1 could restore EMT by antagonizing the role of RAGE. These results may provide a new theoretical basis for EMT and help identify new therapeutic targets for suppressing CKD progression.

Application of Traditional Chinese Medicines in Postoperative Abdominal Adhesion.

Adhesion is a frequent complication after abdominal surgery. Although various methods have been applied to prevent and treat postoperative abdominal adhesion (PAA), few modern drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far. There is an imperative to develop some new strategies for the treatment of PAA. Traditional Chinese medicine (TCM) has been widely practiced for thousands of years and played an indispensable role in the prevention and treatment of diseases. Modern medicine researchers have accepted the therapeutic effects of many active components derived from Chinese medicinal herbs. The review stresses the most commonly used TCM treatment, including Chinese medicinal herbals and monomers, TCM formulas, and acupuncture treatment.

Advanced oxidation protein products upregulate efflux transporter expression and activity through activation of the Nrf-2-mediated signaling pathway in vitro and in vivo.

Clinical and benchtop studies suggest that chronic kidney disease (CKD) alters both renal and nonrenal clearance of drugs. Although studies have documented that the accumulating uremic toxins in the body under CKD conditions are humoral factors that alter the expression and/or activity of drug transporters, the specific process is poorly understood. In this study, we found that advanced oxidation protein products (AOPPs), which are a modified protein uremic toxin, could upregulate efflux transporters, including P-glycoprotein (ABCB1), multi-drug resistance-associated protein 2 (ABCC2) and breast cancer resistance protein (ABCG2) expression in CKD rat models and in HepG2 cells. Our research shows that renal function decline was associated with the accumulation of AOPPs in serum and the upregulation of efflux transporters in the liver in two rat models of CKD. In HepG2 cells, AOPPs significantly increased the expression of efflux transporters in a dose- and time-dependent manner and upregulated the mRNA expression, protein expression and activity of efflux transporters, but bovine serum albumin (BSA), a synthetic precursor of AOPPs, had no effect. This effect correlated with AOPPs activation of the nuclear factor E2-related factor 2 (Nrf-2)-mediated signaling pathway. Further investigation of the regulation of Nrf-2 by AOPPs revealed that ML385 and siNrf-2 abolished the upregulatory effects of AOPPs. These findings suggest that AOPPs upregulate ABCB1, ABCG2 and ABCC2 through Nrf-2 signaling pathways. Protein uremic toxins, such as AOPPs, may modify the nonrenal clearance of drugs in patients with CKD through effects on drug transporters.

Sodium aescinate significantly suppress postoperative peritoneal adhesion by inhibiting the RhoA/ROCK signaling pathway.

BACKGROUND: Although mechanical barriers and modern surgical techniques have been developed to prevent postoperative adhesion formation, high incidence of adhesions still represents an important challenge in abdominal surgery. So far, there has been no available therapeutic drug in clinical practice. PURPOSE: In this study, we explored the efficacy of sodium aescinate (AESS) treatment against postoperative peritoneal adhesions, the potential molecular mechanism was also investigated. STUDY DESIGN AND METHODS: Sixty male Sprague-Dawley rats were randomly divided into 6 groups for the study: the blank, vehicle, positive control and three AESS administration groups (0.5, 1 and 2 mg/kg/d, intravenous administration for 7 days). Adhesions were induced by discretely ligating peritoneal sidewall. An IL-1ß-induced HMrSV5 cell model was also performed to explore possible functional mechanism. RESULTS: The results indicated that the incidence and severity of peritoneal adhesions were significantly lower in the AESS-treated groups than that in the vehicle and positive control group. AESS-treated groups showed that the secretion, activity, and expression of tPA in rat peritoneum were notably increased. The FIB levels in rat plasma were decreased. The immunohistochemical staining analysis demonstrated that collagen I and α-SMA deposition were significantly attenuated in AESS-treated peritoneal tissues. Besides, we found that AESS treatment reduced the protein levels of p-MYPT1. To further explore the mechanisms of AESS, both activator and inhibitors of RhoA/ROCK pathway were employed in this study. It was found that AESS-induced up-regulation of tPA was reversed by activator of ROCK, but the effects of ROCK inhibitors were consistent with AESS. CONCLUSION: Taken together, the findings of in vivo and in vitro experiments proved that AESS could significantly suppress postoperative peritoneal adhesion formation through inhibiting the RhoA/ROCK signaling pathway. Our researches provide important pharmacological basis for AESS development as a potential therapeutic agent on peritoneal adhesions.

The flavonoid-enriched extract from the root of Smilax china L. inhibits inflammatory responses via the TLR-4-mediated signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Smilax china L. has been used clinically to treat various inflammatory disorders with a long history. AIM OF THE STUDY: To investigate the mechanisms underlying anti-inflammatory action of the extract from the herb. MATERIALS AND METHODS: The extract was identified and quantified using the Ultra Performance Liquid Chromatography-Photo Diode Array-Mass Spectrometer method. The anti-inflammatory activities were examined in xylene-induced mouse ear edema and cotton ball-induced rat granuloma. The inflammatory mediators, pro-inflammatory cytokines and TLR-4-mediated signals in LPS-stimulated RAW264.7 macrophages were determined using ELISA, real-time PCR, Western blot and/or immunofluorescence, respectively. RESULTS: The extract was found to enrich flavonoids (44.3%, mainly astilbin, engeletin, isoastilbin, cinchonain Ia, quercetin-3-O-a-L-rhamnopyranoside and chlorogenic acid). The flavonoid-enriched extract (FEE) inhibited xylene-induced mouse ear edema and cotton ball-induced rat granuloma, and suppressed LPS-induced over-release and/or overexpression of tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase, interleukin-1ß and interleukin-6 in RAW264.7 macrophages. Mechanistically, FEE suppressed protein overexpression of TLR-4 and its downstream signals, MyD88 protein, phosphorylated inhibitory κB-α, NF-κB-P65 and MAPK p38, as well as phosphorylation of phosphoinositide 3-kinase (PI3K) p85α at Tyr607 and Akt at Ser473 in LPS-stimulated macrophages. The mode of the anti-inflammatory action of FEE was similar to that of TAK-242 (a selective TLR-4 inhibitor). CONCLUSIONS: The present results demonstrate that FEE inhibit inflammatory responses via the TLR-4-mediated signaling pathway. Our findings go a new insight into the mechanisms underlying anti-inflammatory action of the herb, and provide a better understanding of its use for inflammatory diseases.

Yinning Tablet, a hospitalized preparation of Chinese herbal formula for hyperthyroidism, ameliorates thyroid hormone-induced liver injury in rats: Regulation of mitochondria-mediated apoptotic signals.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperthyroidism is closely associated with liver injury. The preliminary clinical observation suggests that Yinning Tablet, a hospitalized preparation of traditional Chinese formula for hyperthyroidism, improves not only hyperthyroidism, but also hyperthyroidism-associated liver injury. AIM: To evaluate the effect and underlying mechanisms of Yinning Tablet on thyroid hormone-induced liver injury. MATERIALS AND METHODS: Female rats were orally administered L-thyroxine (1 mg/kg) once daily for 60 days, and co-treated with the carefully identified Yinning Tablet extract (0.6-2.4 g/kg) during the last 30 days. Blood and liver variables were determined enzymatically, histologically, by ELISA, radioimmunoassay, Real-Time PCR or Western blot, respectively. RESULTS: Co-treatment with the extract attenuated L-thyroxine-induced increases in serum alanine transaminase and aspartate transaminase activities, the ratio of liver weight to body weight, cytoplasmic vacuolization in hepatocytes, infiltrated inflammatory cells and confused structures in liver tissue, accompanied by attenuation of increased serum triiodo-l-thyronine concentration and hepatic deiodinase type I overexpression in rats. Importantly, Yinning Tablet suppressed L-thyroxine-triggered hepatic Bax, cleaved caspases-3, -8 and -9 protein overexpression, and Bcl-2 protein downregulation. Furthermore, the increases in cytochrome c protein expression, Ca2+-ATPase activity and malondialdehyde content, and decreases in activities of Na+/K+-ATPase, catalase, superoxide dismutase and glutathione peroxidase, and total antioxidant capacity in liver tissue were attenuated. CONCLUSION: The present results suggest that Yinning Tablet ameliorates thyroid hormone-induced liver injury in rats by regulating mitochondria-mediated apoptotic signals. Our findings go insight into the pharmacological basis of the hospitalized preparation for treatment of hyperthyroidism-associated liver injury.

Pillar-Layered Metal-Organic Framework with Sieving Effect and Pore Space Partition for Effective Separation of Mixed Gas C2H2/C2H4.

The removal of acetylene from the industrial feed gas to purify the ethylene is an important and challenging issue. The adsorption-based separation is a more environmentally friendly and cost-effective method compared to the current removal approaches such as partial hydrogenation and solvent extraction, while facing the challenge of developing materials with high C2H2/C2H4 selectivity and C2H2 capacity. Herein, by expanding mixed-metal organic frameworks (M'MOFs) structure with high C2H2/C2H4 selectivity, we report a pillar-layered MOF, {[Cd5(MPCZ)2(BDC)3(NO3)2(H2O)4]·G}n (MECS-5), which not only inherits the sieving effects of M'MOF series but also develops its own characteristic-the 2D layer with expanding space and the plane pore-partition group to "cover" it. MECS-5 shows higher ideal adsorption solution theory C2H2/C2H4 selectivity than the most reported MOFs, especially more than 5 times higher than MOF-74 series while displaying great enhancement in the C2H2 capacity, more than 2 times higher compared to the M'MOF. The column breakthrough experiment further proves the possibility of MECS-5a for real industrial ethylene purification.