Vessels are a critical and necessary component of most tissues, and there has been substantial research investigating vessel formation and stabilization. Several groups have investigated coculturing endothelial cells with a second cell type to promote formation and stabilization of vessels. Some have noted that long-term vessels derived from implanted cocultures are often chimeric consisting of both host and donor cells. The questions arise as to whether the coculture cell might impact the chimeric nature of the microvessels and can modulate the density of donor cells over time. If long-term engineered microvessels are primarily of host origin, any impairment of the host's angiogenic ability has significant implications for the long-term success of the implant. If one can modulate the host versus donor response, one may be able to overcome a host's angiogenic impairment. Furthermore, if one can modulate the donor contribution, one may be able to engineer microvascular networks to deliver molecules a patient lacks systemically for long times. To investigate the impact of the cocultured cell on the host versus donor contributions of endothelial cells in engineered microvascular networks, we varied the ratio of the neural progenitors to endothelial cells in subcutaneously implanted poly(ethylene glycol)/poly-L-lysine hydrogels. We found that the coculture of neural progenitors with endothelial cells led to the formation of chimeric host-donor vessels, and the ratio of neural progenitors has a significant impact on the long term residence of donor endothelial cells in engineered microvascular networks in vivo even though the neural progenitors are only present transiently in the system. We attribute this to the short term paracrine signaling between the two cell types. This suggests that one can modulate the host versus donor contributions using short-term paracrine signaling which has broad implications for the application of engineered microvascular networks and cellular therapy more broadly.
The apoAI mimetic 4F was designed to inhibit atherosclerosis by improving HDL. We reported that treating tight skin (Tsk−/+) mice, a model of systemic sclerosis (SSc), with 4F decreases inflammation and restores angiogenic potential in Tsk−/+ hearts. Interferon regulating factor 5 (IRF5) is important in autoimmunity and apoptosis in immune cells. However, no studies were performed investigating IRF5 in myocardium. We hypothesize that 4F differentially modulates IRF5 expression and activation in Tsk−/+ hearts. Posterior wall thickness was significantly increased in Tsk−/+ compared to C57Bl/6J (control) and Tsk−/+ mice with 4F treatment assessed by echoradiography highlighting reduction of fibrosis in 4F treated Tsk−/+ mice. IRF5 in heart lysates from control and Tsk/+ with and without 4F treatment (sc, 1 mg/kg/d, 6–8 weeks) was determined. Phosphoserine, ubiquitin, ubiquitin K63 on IRF5 were determined on immunoprecipitates of IRF5. Immunofluorescence and TUNEL assays in heart sections were used to determine positive nuclei for IRF5 and apoptosis, respectively. Fluorescence-labeled streptavidin (SA) was used to determine endothelial cell uptake of biotinylated 4F. SA-agarose pulldown and immunoblotting for IRF5 were used to determine 4F binding IRF5 in endothelial cell cytosolic fractions and to confirm biolayer interferometry studies. IRF5 levels in Tsk−/+ hearts were similar to control. 4F treatments decrease IRF5 in Tsk−/+ hearts and decrease phosphoserine and ubiquitin K63 but increase total ubiquitin on IRF5 in Tsk−/+ compared with levels on IRF5 in control hearts. 4F binds IRF5 by mechanisms favoring association over dissociation strong enough to pull down IRF5 from a mixture of endothelial cell cytosolic proteins. IRF5 positive nuclei and apoptotic cells in Tsk−/+ hearts were increased compared with controls. 4F treatments decreased both measurements in Tsk−/+ hearts. IRF5 activation in Tsk−/+ hearts is increased. 4F treatments decrease IRF5 expression and activation in Tsk−/+ hearts by a mechanism related to 4F’s ability to bind IRF5.
Reactive gliosis had been implicated in injury and recovery patterns associated with hydrocephalus. Our aim is to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce reactive gliosis and inhibit the development of hydrocephalus.
The ventricular dilatation were evaluated by MRI at 1-week post drugs treated, while GFAP and Iba-1were detected by RT-PCR, Immunohistochemistry and Western blot. The expression of GFAP and Iba-1 was significantly higher in hydrocephalic group compared with saline control group (p < 0.05). Minocycline treatment of hydrocephalic animals reduced the expression of GFAP and Iba-1 significantly (p < 0.05). Likewise, the severity of ventricular dilatation is lower in minocycline treated hydrocephalic animals compared with the no minocycline group (p < 0.05).
Minocycline treatment is effective in reducing the gliosis and delaying the development of hydrocephalus with prospective to be the auxiliary therapeutic method of hydrocephalus.
Hydrocephalus; Gliosis; Astrocytosis; Microgliosis; Minocycline
As a precursor of the potent photosensitizer protoporphyrin IX (PpIX), 5-aminolevulinic acid (5-ALA), was conjugated onto cationic gold nanoparticles (GNPs) to improve the efficacy of photodynamic therapy (PDT).
Cationic GNPs reduced by branched polyethyleneimine and 5-ALA were conjugated onto the cationic GNPs by creating an electrostatic interaction at physiological pH. The efficacy of ALA-GNP conjugates in PDT was investigated under irradiation with a mercury lamp (central wavelength of 395 nm) and three types of light-emitting diode arrays (central wavelengths of 399, 502, and 621 nm, respectively). The impacts of GNPs on PDT were then analyzed by measuring the intracellular PpIX levels in K562 cells and the singlet oxygen yield of PpIX under irradiation.
The 2 mM ALA-GNP conjugates showed greater cytotoxicity against K562 cells than ALA alone. Light-emitting diode (505 nm) irradiation of the conjugates caused a level of K562 cell destruction similar to that with irradiation by a mercury lamp, although it had no adverse effects on drug-free control cells. These results may be attributed to the singlet oxygen yield of PpIX, which can be enhanced by GNPs.
Under irradiation with a suitable light source, ALA-GNP conjugates can effectively destroy K562 cells. The technique offers a new strategy of PDT.
nonradiative energy transfer; photodamage; protoporphyrin IX; selective destruction; singlet oxygen sensor green reagent; surface plasmon resonance
Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible enzyme, has been shown to metabolically activate various carcinogens, which is critical for the development and progression of cancers. It has demonstrated that CYP2E1 polymorphisms alter the transcriptional activity of the gene. However, studies on the association between CYP2E1 polymorphisms (PstI/RsaI or DraI) and gastric cancer have reported conflicting results. Thus, the aim of the present study was to investigate whether CYP2E1 polymorphisms is associated with the development and progression of gastric cancer and its prognosis in Chinese patients.
A case-control study was conducted in which CYP2E1 PstI/RsaI and DraI polymorphisms were analyzed in 510 Chinese patients with gastric cancer and 510 age- and sex- matched healthy controls by PCR-RFLP. Odds ratios were estimated by multivariate logistic regression, and the lifetime was calculated by Kaplan-Meier survival curves. In addition, a meta-analysis was also conducted to verify the findings.
For CYP2E1 PstI/RsaI polymorphism, C2C2 homozygotes (OR = 2.15; CI: 1.18–3.94) and C2 carriers (OR = 1.48; CI: 1.13–1.96) were associated with an increased risk of gastric cancer when compared with C1C1 homozygotes. Both C1C2 and C2C2 genotypes were associated with advanced stage, but not the grade of gastric cancer. Moreover, C2C2 genotype was identified as an independent marker of poor overall survival for gastric cancer. However, there was not any significant association between CYP2E1 DraI polymorphism and the risk of gastric cancer. In the meta-analysis, pooled data from 13 studies confirmed that the CYP2E1 PstI/RsaI polymorphism was associated with a significantly increased risk of gastric cancer.
CYP2E1 PstI/RsaI polymorphism is associated with increased risk of development, progression and poor prognosis of gastric cancer in Chinese patients. Pooled data from 13 studies, mainly in Asian countries, are in agreement with our findings.
This paper presents an automatic computer-aided detection scheme on digital chest radiographs to detect pneumoconiosis. Firstly, the lung fields are segmented from a digital chest X-ray image by using the active shape model method. Then, the lung fields are subdivided into six non-overlapping regions, according to Chinese diagnosis criteria of pneumoconiosis. The multi-scale difference filter bank is applied to the chest image to enhance the details of the small opacities, and the texture features are calculated from each region of the original and the processed images, respectively. After extracting the most relevant ones from the feature sets, support vector machine classifiers are utilized to separate the samples into the normal and the abnormal sets. Finally, the final classification is performed by the chest-based report-out and the classification probability values of six regions. Experiments are conducted on randomly selected images from our chest database. Both the training and the testing sets have 300 normal and 125 pneumoconiosis cases. In the training phase, training models and weighting factors for each region are derived. We evaluate the scheme using the full feature vectors or the selected feature vectors of the testing set. The results show that the classification performances are high. Compared with the previous methods, our fully automated scheme has a higher accuracy and a more convenient interaction. The scheme is very helpful to mass screening of pneumoconiosis in clinic.
Pneumoconiosis; digital radiography; computer-aided detection (CAD); active shape model (ASM); texture analysis; support vector machine (SVM)
Exposure to diesel exhaust particles (DEPs), a major source of traffic-related air pollution, has become a serious health concern due to its adverse influences on human health including cardiovascular and respiratory disorders. To elucidate the relationship between biophysical properties (cell topography, cytoskeleton organizations, and cell mechanics) and functions of endothelial cells exposed to DEPs, atomic force microscope (AFM) was applied to analyze the toxic effects of DEPs on a model cell line from human aortic endothelial cells (HAECs). Fluorescence microscopy and flow cytometry were also applied to further explore DEP-induced cytotoxicity in HAECs. Results revealed that DEPs could negatively impair cell viability and alter membrane nanostructures and cytoskeleton components in a dosage- and a time-dependent manner; and analyses suggested that DEPs-induced hyperpolarization in HAECs appeared in a time-dependent manner, implying DEP treatment would lead to vasodilation, which could be supported by down-regulation of cell biophysical properties (e.g., cell elasticity). These findings are consistent with the conclusion that DEP exposure triggers important biochemical and biophysical changes that would negatively impact the pathological development of cardiovascular diseases. For example, DEP intervention would be one cause of vasodilation, which will expand understanding of biophysical aspects associated with DEP cytotoxicity in HAECs.
The American Diabetes Association and World Health Organization have recently adopted the HbA1c measurement as one method of diagnostic criteria for diabetes. The change in diagnostic criteria has important implications for diabetes treatment and prevention. We therefore investigate diabetes using HbA1c and glucose criteria together, and assess the prevalent trend in a developing southern Chinese population with 85 million residents.
A stratified multistage random sampling method was applied and a representative sample of 3590 residents 18 years of age or above was obtained in 2010. Each participant received a full medical check-up, including measurement of fasting plasma glucose, 2-hour post-load plasma glucose, and HbA1c. Information on history of diagnosis and treatment of diabetes was collected. The prevalence of diabetes obtained from the present survey was compared with the data from the survey in 2002.
The prevalence of diabetes based on both glucose and HbA1c measurements was 21.7% (95% CI: 17.4%–26.1%) in 2010, which suggests that more than 1 in 5 adult residents were suffering from diabetes in this developing population. Only 12.9% (95% CI: 8.3%–17.6%) of diabetic residents were aware of their condition. The prevalence of pre-diabetes was 66.3% (95% CI: 62.7%–69.8%). The prevalence of diabetes and pre-diabetes which met all the three diagnostic thresholds (fast plasma glucose, 2 hour post-load plasma glucose, and HbA1c) was 3.1% and 5.2%, respectively. Diabetes and pre-diabetes as determined by HbA1c measurement had higher vascular risk than those determined by glucose levels. The prevalence of diabetes increased from 2.9% (95% CI: 2.0%–3.7%) in 2002 to 13.8% (95% CI: 10.2%–17.3%) in 2010 based on the same glucose criteria.
Our results show that the diabetes epidemic is accelerating in China. The awareness of diabetes is extremely low. The glucose test and HbA1c measurement should be used together to increase detection of diabetes and pre-diabetes.
We report a novel inhibitor that selectively suppresses dengue virus (DENV) by targeting viral NS4B protein. The inhibitor was identified by screening a 1.8-million-compound library using a luciferase replicon of DENV serotype 2 (DENV-2). The compound specifically inhibits all four serotypes of DENV (50% effective concentration [EC50], 1 to 4 μM; and 50% cytotoxic concentration [CC50], >40 μM), but it does not inhibit closely related flaviviruses (West Nile virus and yellow fever virus) or nonflaviviruses (Western equine encephalomyelitis virus, Chikungunya virus, and vesicular stomatitis virus). A mode-of-action study suggested that the compound inhibits viral RNA synthesis. Replicons resistant to the inhibitor were selected in cell culture. Sequencing of the resistant replicons revealed two mutations (P104L and A119T) in the viral NS4B protein. Genetic analysis, using DENV-2 replicon and recombinant viruses, demonstrated that each of the two NS4B mutations alone confers partial resistance and double mutations confer additive resistance to the inhibitor in mammalian cells. In addition, we found that a replication defect caused by a lethal NS4B mutation could be partially rescued through trans complementation. The ability to complement NS4B in trans affected drug sensitivity when a single cell was coinfected with drug-sensitive and drug-resistant viruses. Mechanistically, NS4B was previously shown to interact with the viral NS3 helicase domain; one of the two NS4B mutations recovered in our resistance analysis—P104L—abolished the NS3-NS4B interaction (I. Umareddy, A. Chao, A. Sampath, F. Gu, and S. G. Vasudevan, J. Gen. Virol. 87:2605-2614, 2006). Collectively, the results suggest that the identified inhibitor targets the DENV NS4B protein, leading to a defect in viral RNA synthesis.
Velvet antler of deer (VAD) is a commonly-used kidney-Yang supplementing traditional Chinese medication. According to the heart-kidney-related theory, heart Yang originates in kidney Yang and heart failure due to heart Yang deficiency can be treated by tonifying kidney Yang. In this study, we investigated therapeutic effects of VAD on cardiac functions in rats with heart failure following myocardial infarction. Forty-eight male Wistar rats were subjected either to left coronary artery ligation (N = 36) or to sham operation (N = 12). One week after the surgery, rats with heart failure received daily treatment of double-distilled water, captopril or VAD by gavage for consecutively four weeks, while sham-operated animals were given double-distilled water. Ultrasonic echocardiography was adopted to examine cardiac structural and functional parameters and serum brain natriuretic peptide (BNP) concentration was measured using radioimmunoassay. We found that VAD partially reversed changes in cardiac functional parameters and serum BNP levels in rats with heart failure. These results provide further evidence for the heart-kidney-related theory and suggest that VAD might be a potentially alternative and complementary medicine for the treatment of heart failure.
Objective. The aim of this overview was to summarize the outcome measures of Chinese herbal medicine (CHM) as the treatment of coronary heart disease (CHD) based on available systematic reviews (SRs), so as to display the current situation and evaluate the potential benefits and advantages of CHM on CHD. Methods. An extensive search included the Cochrane Database of Systematic Reviews, MEDLINE, and 4 databases in Chinese. SRs of CHM for CHD were included. Besides evaluating and summarizing the outcome measures, we also estimated the quality of the included reviews by PRISMA (preferred reporting items for systematic reviews and meta-analyses). Data were extracted according to predefined inclusion criteria by two independent reviewers. Results. 46 articles were included. 20 kinds of CHM were reviewed. 7 SRs were concerned with myocardial infarction (MI), 38 SRs were related to angina pectoris. 11 SRs had primary endpoints, while others focused on secondary endpoints to evaluate CHM for CHD such as angina pectoris and electrocardiogram (ECG). One SR reported more adverse effects of CHM for CHD and of the SRs analyzed quality of life. Many CHM appeared to have significant effect on improving symptoms, ECG, biomarkers and so on. However, most SRs failed to make a definite conclusion for the effectiveness of CHM in CHD patients due specifically to the poor evidence. And according to PRISMA we found most of the trials in the SRs were of low quality. Conclusion. Primary endpoints were not used widely. The benefits of CHM for CHD need to be confirmed in the future with RCTs of more persuasive primary endpoints and high-quality SRs.
Objective. To evaluate the effectiveness of astragalus injection (a traditional Chinese patent medicine) for patients with renal damage induced by hypertension according to the available evidence. Methods. We searched MEDLINE, China National Knowledge Infrastructure (CNKI), Chinese VIP Information, China Biology Medicine (CBM), and Chinese Medical Citation Index (CMCI), and the date of search starts from the first of database to August 2011. No language restriction was applied. We included randomized controlled trials testing astragalus injection against placebo or astragalus injection plus antihypertensive drugs against antihypertensive drugs. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane review standards. Results. 5 randomized trials (involving 429 patients) were included and the methodological quality was evaluated as generally low. The pooled results showed that astragalus injection was more effective in lowering β2-microglobulin (β2-MG), microalbuminuria (mAlb) compared with placebo, and it was also superior to prostaglandin in lowering blood urea nitrogen (BUN), creatinine clearance rate (Ccr). There were no adverse effects reported in the trials from astragalus injection. Conclusions. Astragalus injection showed protective effects in hypertensive renal damage patients, although available studies are not adequate to draw a definite conclusion due to low quality of included trials. More rigorous clinical trials with high quality are warranted to give high level of evidence.
It is well known that antioxidants have protective effects against oxidative stress. Unfortunately, in the presence of transition metals, antioxidants including polyphenols with potent antioxidant activities may also exhibit pro-oxidant effects, which may irreversibly damage DNA. Therefore, antioxidants with strong free radical scavenging abilities and devoid of pro-oxidant effects would be of immense biological importance. We report two antioxidant dendrimers with a surface rich in multiple phenolic hydroxyl groups, benzylic hydrogens and electron donating ring substituents that contribute to their potent free radical quenching property. In order to minimize their pro-oxidant effects, the dendrimers were designed with a metal chelating tris(2-aminoethyl)amine (TREN) core. The dendritic antioxidants were prepared by attachment of six syringaldehyde or vanillin molecules to TREN by reductive amination. They exhibited potent radical scavenging properties: 5 times stronger than quercetin and 15 times more potent than Trolox according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The antioxidant dendrimers also protected low-density lipoprotein, lysozyme and DNA against 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced free radical damage. More importantly, unlike quercetin and Trolox, the two TREN antioxidant dendrimers did not damage DNA via their pro-oxidant effects when incubated with physiological amounts of copper ions. The dendrimers also showed no cytotoxicity towards Chinese hamster ovary cells.
Polyphenolic dendrimer; antioxidant; pro-oxidant; lipoprotein; lysozyme; DNA
Objective. This systematic review aims to evaluate the benefit and side effect of Xuezhikang for coronary heart disease (CHD) complicated by dyslipidemia. Methods. All randomized clinical trials (RCTs) with Xuezhikang as a treatment for CHD combined with dyslipidemia were considered for inclusion. Data extraction and analyses and quality assessment were conducted according to the Cochrane standards. Results. We included 22 randomized trials. Xuezhikang showed significant benefit on the incidence of all-cause deaths, CHD deaths, myocardial infarction, and revascularization as compared with placebo based on conventional treatment for CHD. It remarkably lowered total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) as compared with the placebo or inositol nicotinate group, which was similar to statins group. Xuezhikang also raised high-density lipoprotein cholesterol (HDL-C) compared to placebo or no intervention, which was similar to Inositol nicotinate and slightly inferior to statins. The incidence of adverse events did not differ between the Xuezhikang and control group. Conclusions. Xuezhikang showed a comprehensive lipid-regulating effect and was safe and effective in reducing cardiovascular events in CHD patients complicated by dyslipidemia. However, more rigorous trials with high quality are needed to give high level of evidence.
Recent understanding of atherosclerosis and coronary heart disease has shifted the focus from lumen stenosis to vulnerable plaque, from lipid deposit to inflammatory reaction, and from vulnerable plaque to vulnerable patient. This has led to a new direction of treatment consisting of intervening the inflammatory reaction, stabilizing the vulnerable plaque, inhibiting thrombosis after plaque rupture, and treating the vulnerable patient instead of treating lumen stenosis. This seems to mirror the traditional Chinese medicine (TCM) focus on prevention and on the vulnerable patient with treatment matched to the pattern dysfunction and dysregulation using the Chinese herbal medicine multitargeted approach. Given the convergence of both the East and the West conceptualization of atherosclerosis, it is hopeful that the integrative East-West approach will facilitate early detection and more effective treatment of the vulnerable patients with coronary heart disease.
Regional elevations in cerebral blood flow (CBF) often occur in response to localized increases in cerebral neuronal activity. An ever expanding literature has linked this neurovascular coupling process to specific signaling pathways involving neuronal synapses, astrocytes and cerebral arteries and arterioles. Collectively, these structures are termed the “neurovascular unit” (NVU). Astrocytes are thought to be the cornerstone of the NVU. Thus, not only do astrocytes “detect” increased synaptic activity, they can transmit that information to proximal and remote astrocytic sites often through a Ca2+-and ATP-related signaling process. At the vascular end of the NVU, a Ca2+-dependent formation and release of vasodilators, or substances linked to vasodilation, can occur. The latter category includes ATP, which upon its appearance in the extracellular compartment, can be rapidly converted to the potent vasodilator, adenosine, via the action of ecto-nucleotidases. In the present review, we give consideration to experimental model-specific variations in purinergic influences on gliovascular signaling mechanisms, focusing on the cerebral cortex. In that discussion, we compare findings obtained using in vitro (rodent brain slice) models and multiple in vivo models (2-photon imaging; somatosensory stimulation–evoked cortical hyperemia; and sciatic nerve stimulation-evoked pial arteriolar dilation). Additional attention is given to the importance of upstream (remote) vasodilation; the key role played by extracellular ATP hydrolysis (via ecto-nucleotidases) in gliovascular coupling; and interactions among multiple signaling pathways.
adenosine; neurovascular unit; astrocyte; glia limitans; cerebral blood flow
Objective. The aim of this overview was to evaluate and summarize Cochrane reviews of traditional Chinese herbal products (TCHPs) as the treatment for coronary heart disease (CHD). Methods. We searched the Cochrane Database that was concerned with the effectiveness of TCHPs for CHD. We also searched the Cochrane Central Register of Controlled Trials. Reviews and primary studies of TCHP as the treatment of any type of CHD were included. Data were extracted according to predefined inclusion criteria by two independent reviewers. Results. Six Cochrane reviews were included. They related to a wide range of TCHPs for different types of CHD. Four reviews were concerned with angina pectoris (unstable or stable), one review was concerned with heart failure, and for acute myocardial infarction. No reviews concluded that TCHPs were definitely effective for CHD because of the weak evidence. Eight primary studies were TCHPs from CHD. These studies also maybe result in bias, but better than before. Conclusion. Several Cochrane reviews of TCHPs for the treatment of different types of CHD have recently been published. None of these reviews got definite conclusion favoring the effectiveness of TCHPs due to the weak evidence. With the improved quality of the new registered RCTs. The potential role of TCHPs in treating CHD is anticipated to be detected.
GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin biosynthesis and has been shown to be a promising therapeutic target in ischemic heart disease, hypertension, atherosclerosis and diabetes. The endogenous GCH1-interacting partners have not been identified. Here, we determined endogenous GCH1-interacting proteins in rat.
Methods and Results
A pulldown and proteomics approach were used to identify GCH1 interacting proteins in rat liver, brain, heart and kidney. We demonstrated that GCH1 interacts with at least 17 proteins including GTP cyclohydrolase I feedback regulatory protein (GFRP) in rat liver by affinity purification followed by proteomics and validated six protein partners in liver, brain, heart and kidney by immunoblotting. GCH1 interacts with GFRP and very long-chain specific acyl-CoA dehydrogenase in the liver, tubulin beta-2A chain in the liver and brain, DnaJ homolog subfamily A member 1 and fatty aldehyde dehydrogenase in the liver, heart and kidney and eukaryotic translation initiation factor 3 subunit I (EIF3I) in all organs tested. Furthermore, GCH1 associates with mitochondrial proteins and GCH1 itself locates in mitochondria.
GCH1 interacts with proteins in an organ dependant manner and EIF3I might be a general regulator of GCH1. Our finding indicates GCH1 might have broader functions beyond tetrahydrobiopterin biosynthesis.
We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and in vivo. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its in vivo stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a Cmax (maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC90) value of 0.96 μM. In agreement with the in vivo pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.
Improved biodegradable vascular grafts and stents are in demand, particularly for pediatric patients. Poly(l-lactic acid) (PLLA) is an FDA-approved biodegradable polymer of potential use for such applications. However, tissue culture studies have shown that endothelial cell (EC) attachment and growth occurs relatively slowly on PLLA surfaces. This slow growth has been attributed to the fact that PLLA represents a hydrophobic substrate, relatively devoid of active functional groups. As a result, the slow EC recovery on the luminal side of PLLA stents provides an increased risk of induced thrombosis. In the present study, surface modification of PLLA substrates has been examined as a potential route to enhance EC growth. For this purpose, PLLA surfaces were modified via pulsed plasma deposition of thin films of poly(vinylacetic acid). The –COOH surface groups, introduced by the plasma deposition, were employed to conjugate fibronectin (FN), followed by attachment of vascular endothelial growth factor to FN. Pig Aorta ECs (PAE) and kinase-insert domain-containing receptor (KDR)-transfected PAE showed increased cell adhesion and proliferation, as well as substantially improved cell retention under fluidic shear stress on surface-modified PLLA compared with untreated PLLA. Although KDR-transfected PAE exhibited better cell proliferation than PAE, normal EC functions, including EC morphology, nitric oxide production, and KDR expression, were observed when cells were grown on surface-modified PLLA. The results obtained clearly indicate that this combined surface modification technique using poly(vinylacetic acid) deposition, FN conjugation, and vascular endothelial growth factor surface delivery can enhance endothelialization on PLLA, particularly when employed in conjunction with the growth of KDR-transfected ECs.
Tanshinone IIA (Tan IIA) is a member of the major lipophilic components extracted from the root of Salvia miltiorrhiza Bunge, which is currently used in China and other neighboring countries to treat patients suffering from myocardial infarction (MI), angina pectoris, stroke, diabetes, sepsis, and other conditions. However, Tan IIA is not easy to be absorbed through intestinal pathway. To raise the bioavailability of the herb, sodium tanshinone IIA sulfonate (STS) was developed. This paper discussed the pharmacology of Tan IIA, STS, and their potential cardioprotective effects.
The metabolic syndrome has been shown to increase the incidence of cardiovascular disease. Little information exists on the prevalence of the metabolic syndrome for southern Chinese. We therefore investigate the prevalence of the metabolic syndrome in a southern Chinese population with 85 million residents.
The Guangdong Nutrition and Health Survey 2002 is a cross-sectional survey designed to assess the health and nutritional status of 85 million residents in Guangdong province located in southern China. Stratified multistage random sampling method was applied in this survey and a provincial representative sample of 6,468 residents aged 20 years or above was obtained in the present study. The participants received a full medical check-up including measurement of blood pressure, obesity indices, fasting lipids and glucose levels. Data describing socioeconomic and lifestyle factors was also collected through interview. Metabolic syndrome was defined in accordance with the International Diabetes Federation criteria.
The prevalence of metabolic syndrome was 7.30%, translating into a total of 4.0 million residents aged 20 years or above having the condition in this southern Chinese population. The urban population had higher prevalence of the syndrome than the rural population (10.57% vs 4.30%). Females had a higher prevalence of metabolic syndrome than males (8.99% vs 5.27%). More than 60% of the adults had at least one component of the metabolic syndrome.
Our results indicate that a large proportion of southern Chinese adults have the metabolic syndrome and associated risk factors. The metabolic syndrome has become an important public health problem in China. These findings emphasize the urgent need to develop population level strategies for the prevention, detection, and treatment of cardiovascular risk in China.
The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal–promoting effects in human cord blood CD34+ cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.
Viral replication relies on the host to supply nucleosides. Host enzymes involved in nucleoside biosynthesis are potential targets for antiviral development. Ribavirin (a known antiviral drug) is such an inhibitor that suppresses guanine biosynthesis; depletion of the intracellular GTP pool was shown to be the major mechanism to inhibit flavivirus. Along similar lines, inhibitors of the pyrimidine biosynthesis pathway could be targeted for potential antiviral development. Here we report on a novel antiviral compound (NITD-982) that inhibits host dihydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine biosynthesis. The inhibitor was identified through screening 1.8 million compounds using a dengue virus (DENV) infection assay. The compound contains an isoxazole-pyrazole core structure, and it inhibited DENV with a 50% effective concentration (EC50) of 2.4 nM and a 50% cytotoxic concentration (CC50) of >5 μM. NITD-982 has a broad antiviral spectrum, inhibiting both flaviviruses and nonflaviviruses with nanomolar EC90s. We also show that (i) the compound inhibited the enzymatic activity of recombinant DHODH, (ii) an NITD-982 analogue directly bound to the DHODH protein, (iii) supplementing the culture medium with uridine reversed the compound-mediated antiviral activity, and (iv) DENV type 2 (DENV-2) variants resistant to brequinar (a known DHODH inhibitor) were cross resistant to NITD-982. Collectively, the results demonstrate that the compound inhibits DENV through depleting the intracellular pyrimidine pool. In contrast to the in vitro potency, the compound did not show any efficacy in the DENV-AG129 mouse model. The lack of in vivo efficacy is likely due to the exogenous uptake of pyrimidine from the diet or to a high plasma protein-binding activity of the current compound.