Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses.
Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments.
The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2–24.6 nm) and LDL-IVa (23.3–24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values.
Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol.
SKIP is a transcription cofactor in many eukaryotes. It can regulate plant stress tolerance in rice and Arabidopsis. But the homolog of SKIP protein in soybean has been not reported up to now.
In this study, the expression patterns of soybean GAMYB binding protein gene (GmGBP1) encoding a homolog of SKIP protein were analyzed in soybean under abiotic stresses and different day lengths. The expression of GmGBP1 was induced by polyethyleneglycol 6000, NaCl, gibberellin, abscisic acid and heat stress. GmGBP1 had transcriptional activity in C-terminal. GmGBP1 could interact with R2R3 domain of GmGAMYB1 in SKIP domain to take part in gibberellin flowering pathway. In long-day (16 h-light) condition, transgenic Arabidopsis with the ectopic overexpression of GmGBP1 exhibited earlier flowering and less number of rosette leaves; Suppression of AtSKIP in Arabidopsis resulted in growth arrest, flowering delay and down-regulation of many flowering-related genes (CONSTANS, FLOWERING LOCUS T, LEAFY); Arabidopsis myb33 mutant plants with ectopic overexpression of GmGBP1 showed the same flowering phenotype with wild type. In short-day (8 h-light) condition, transgenic Arabidopsis plants with GmGBP1 flowered later and showed a higher level of FLOWERING LOCUS C compared with wild type. When treated with abiotic stresses, transgenic Arabidopsis with the ectopic overexpression of GmGBP1 enhanced the tolerances to heat and drought stresses but reduced the tolerance to high salinity, and affected the expressions of several stress-related genes.
In Arabidopsis, GmGBP1 might positively regulate the flowering time by affecting CONSTANS, FLOWERING LOCUS T, LEAFY and GAMYB directly or indirectly in photoperiodic and gibberellin pathways in LDs, but GmGBP1 might represse flowering by affecting FLOWERING LOCUS C and SHORT VEGETATIVE PHASE in autonomous pathway in SDs. GmGBP1 might regulate the activity of ROS-eliminating to improve the resistance to heat and drought but reduce the high-salinity tolerance.
GmGBP1; Abiotic stress; Flowering; Day-length; Gibberellin
The adaptations of root morphology, physiology, and biochemistry to phosphorus supply have been characterized intensively. However, characterizing these adaptations at molecular level is largely neglected under field conditions. Here, two consecutive field experiments were carried out to investigate the agronomic traits and root traits of wheat (Triticum aestivum L.) at six P-fertilizer rates. Root samples were collected at flowering to investigate root dry weight, root length density, arbusular-mycorrhizal colonization rate, acid phosphatase activity in rhizosphere soil, and expression levels of genes encoding phosphate transporter, phosphatase, ribonucleases, and expansin. These root traits exhibited inducible, inhibitory, or combined responses to P deficiency, and the change point for responses to P supply was at or near the optimal P supply for maximum grain yield. This research improves the understanding of mechanisms of plant adaptation to soil P in intensive agriculture and provides useful information for optimizing P management based on the interactions between soil P dynamics and root processes.
Agronomic trait; phosphatase; phosphate-starvation response; phosphate transporter; phosphorus fertilizer; root morphology; Triticum aestivum L.
Objective: To evaluate the safety and therapeutic efficacy of target percutaneous laser disc decompression (T-PLDD) for the treatment of lumbar disc herniation. Background data: PLDD using the Nd:YAG laser has been regarded as an effective alternative treatment for disc herniation. However, all the previous studies were concentrated on vaporizing the nucleus pulposus in the intervertebral space. We hypothesize that insertion of the needle into the extruded part of the nucleus pulposus will decrease its volume and provide superior clinical effects compared to therapies that decrease the volume of the intradiscal nucleus pulposus. Materials and methods: A total of 25 patients suffering from posterolateral extruded but nonsequestered lumbar intervertebral disc herniation were treated with T-PLDD. After treatment, the patients were followed up and the therapeutic effect was assessed at 1, 3, 6, and 12 months using the modified MacNab criteria. Results: The success rate was 80.0% (18 of 25), 88.0% (22 of 25), 92.0% (23 of 25), and 92.0% (23 of 25) at 1, 3, 6, and 12 months respectively. No serious complications occurred in any of the patients. Furthermore, we did not observe any neurological sequelae. Conclusions: T-PLDD can significantly decrease pain and improve function of patients who have extruded but nonsequestered lumbar intervertebral disc herniation.
Objective and methods: This study established a simple stereological method to obtain quantitative information about two- or three-dimensional structures based on observations from kidney sections in the unilateral ureteral obstruction(UUO) model. Results: Tubulointerstitial area(TA) and TA/the area of a rectangular field(RA) were raised gradually, but significantly, in the obstructed kidney from 1 to 3months post-ligation in comparison to the sham kidney of sham-operated rats(SOR). On the contrary, glomerular area(GA) and glomerular volume(GV) were decreased progressively over time, but significantly, in the obstructed kidney from 3weeks to 3months post-ligation compared to the sham kidney of SOR. UUO caused a progressive decline of TA and TA/RA in the contralateral kidney. More specifically, there were significant decreases in TA at 1,2,3months post-ligation, while in TA/RA only at 3months post-ligation in comparison to the right kidney of SOR. In contrast, GA and GV enhanced in a time-dependent manner in the contralateral kidney, in which the difference in GA reached significance only at 3months post-ligation, whereas the difference in GV reached significance from 1 to 3months post-ligation when comparing with the right kidney of SOR. Conclusions: Our results confirmed two typical features of obstructive nephropathy, including widen interstitial space and glomerular atrophy in the obstructed kidney, and compensatory growth of the contralateral kidney.
Compensatory hypertrophy; kidney section; stereological method; unilateral ureteral obstruction; Wistar rat.
The current guidelines for treatment of high-risk of lipid disorders do not specify a therapeutic target level of HDL-C for prevention of vascular disease in high-risk populations. However, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials, providing the strong, consistent message that raising HDL-C by therapeutic means will effectively and independently reduce cardiovascular risk.
This review summarizes epidemiologic evidence and the results of a meta-analysis of 23 published, prospective, randomized, placebo-controlled clinical trials. It focuses on the effects of lipid therapies on coronary stenosis progression, as measured by quantitative arteriography and/or, on clinical cardiovascular endpoints.
Among the 7 drug/treatment classes into which individual study results were categorized and averaged, reduction in stenosis progression and reduction in clinical events are both very highly correlated with the composite lipid variable (%ΔHDL-C - %ΔLDL-C; where %Δ is percent change relative to the placebo group response). This holds true for all lipid drug classes or combinations of lipid drug therapy, with the exception of the unexpectedly anomalous effects of the torcetrapib-atorvastatin combination.
There is a strong and consistent body of evidence that therapeutic HDL-C-raising is at least as effective as comparable percentages of LDL-C-lowering for reduction of atherosclerosis progression or clinical cardiovascular events overa broad range of risk levels. Adoption of this strategy into guidelines probably awaits results of at least one large controlled HDL-C-raising clinical trial, of which two are ongoing and one other is planned.
HDL-cholesterol; atherosclerosis; fenofibrate; niacin; torcetrapib; heart disease prevention
The endotoxin level in the portal and peripheral veins of hepatocellular carcinoma (HCC) patients is higher and lipopolysaccharide (LPS), a cell wall constituent of gram-negative bacteria, has been reported to inhibit tumor growth. However, in this study, we found that LPS-induced toll-like receptor 4 (TLR4) signaling was involved in tumor invasion and survival, and the molecular mechanism was investigated,
Four HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasion ability of LPS-induced HCC cells and the epithelia-mesenchymal transition (EMT) in vitro and in vivo. A total of 106 clinical samples from HCC patients were used to evaluate TLR4 expression and analyze its association with clinicopathological characteristics
The in vitro and in vivo experiments demonstrated that LPS could significantly enhance the invasive potential and induce EMT in HCC cells with TLR4 dependent. Further studies showed that LPS could directly activate nuclear factor kappa B (NF-κB) signaling through TLR4 in HCC cells. Interestingly, blocking NF-κB signaling significantly inhibited transcription factor Snail expression and thereby inhibited EMT occurrence. High expression of TLR4 in HCC tissues was strongly associated with both poor cancer-free survival and overall survival in patients.
Our results indicate that TLR4 signaling is required for LPS-induced EMT, tumor cell invasion and metastasis, which provide molecular insights for LPS-related pathogenesis and a basis for developing new strategies against metastasis in HCC.
Toll-like receptor 4; Epithelial-mesenchymal transition; Lipopolysaccharide; Human hepatocellular carcinoma
In response to inflammation, mesenchymal stem cells (MSCs) are known to migrate to tissue injury sites to participate in immune modulation, tissue remodeling and wound healing. Tumors apply persistent mechanical and pathological stress to tissues and causes continual infiltration of MSCs. Here, we demonstrate that MSCs promote human hepatocellular carcinoma (HCC) metastasis under the influence of inflammation. The metastasis promoting effect could be imitated with the supernatant of MSCs pretreated with IFNγ and TNFα. Interestingly, treatment of HCC cells with the supernatant leads to epithelial-mesenchymal transition (EMT), an effect related to the production of TGFβ by cytokines stimulated MSCs. Importantly, the levels of MSCs expressing SSEA4 in clinical HCC samples significantly correlated with poor prognosis of HCC, and EMT of HCC was strongly associated with a shorter cancer-free interval (CFI) and a worse overall survival (OS). Therefore, our results suggest that MSCs in tumor inflammatory microenvironment could promote tumor metastasis through TGFβ-induced EMT.
Colorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet.
Flow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The 'stemness' and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133+CXCR4+ cancer cells and patient survival.
In human specimens, the content of CD133+CXCR4+ cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133+ cells in the HCT116 cell line, with CXCR4 expression having no impact on the 'stemness' properties. We found that CD133+CXCR4+ cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133+CXCR4- cells, CD133+CXCR4+ cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133+CXCR4+ cancer cells and enhance their invasive behavior, while this could not be observed in CD133+CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133+CXCR4+ cells in human primary CRC was associated with a reduced two-year survival rate.
Strategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.
colorectal cancer; cancer stem cell; CXCR4; epithelial-mesenchymal transition; liver metastasis
New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 3′-processing.
HIV-1 integrase; inhibit; Raltegravir; cycloaddition
With the U.S. Food and Drug Administration approval of raltegravir (RAL; MK-0518; Merck & Co.), HIV-1 integrase (IN) is the newest therapeutic target for AIDS and HIV infections. Recent structural analyses show that IN strand transfer inhibitors (INSTIs) share a common binding mode in the enzyme active site. While RAL represents a therapeutic breakthrough, the emergence of IN resistance mutations imposes the development of new INSTIs. We report here the biochemical and antiviral activities of MK-0536, a new IN inhibitor. We demonstrate that, like RAL, MK-0536 is highly potent against recombinant IN and viral replication. It is also effective against INs that carry the three main RAL resistance mutations (Y143R, N155H, and to a lesser extent G140S-Q148H) and against the G118R mutant. Modeling of IN developed from recent prototype foamy virus structures is presented to account for the differences in the drug activities of MK-0536 and RAL against the IN mutants.
Cost consequences analysis was completed from randomized controlled trial (RCT) data for the Just-in-time (JIT) librarian consultation service in primary care that ran from October 2005 to April 2006. The service was aimed at providing answers to clinical questions arising during the clinical encounter while the patient waits. Cost saving and cost avoidance were also analyzed. The data comes from eighty-eight primary care providers in the Ottawa area working in Family Health Networks (FHNs) and Family Health Groups (FHGs).
We conducted a cost consequences analysis based on data from the JIT project . We also estimated the potential economic benefit of JIT librarian consultation service to the health care system.
The results show that the cost per question for the JIT service was $38.20. The cost could be as low as $5.70 per question for a regular service. Nationally, if this service was implemented and if family physicians saw additional patients when the JIT service saved them time, up to 61,100 extra patients could be seen annually. A conservative estimate of the cost savings and cost avoidance per question for JIT was $11.55.
The cost per question, if the librarian service was used at full capacity, is quite low. Financial savings to the health care system might exceed the cost of the service. Saving physician's time during their day could potentially lead to better access to family physicians by patients. Implementing a librarian consultation service can happen quickly as the time required to train professional librarians to do this service is short.
Heart failure (HF) is a common and serious comorbidity of diabetes. Oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. The ability of antioxidants to inhibit injury has raised the possibility of new therapeutic treatment for diabetic heart diseases. Riboflavin constitutes an essential nutrient for humans and animals and it is an important food additive. Riboflavin, a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), enhances the oxidative folding and subsequent secretion of proteins. The objective of this study was to investigate the cardioprotective effect of riboflavin in diabetic rats. Diabetes was induced in 30 rats by a single injection of streptozotocin (STZ) (70 mg /kg). Riboflavin (20 mg/kg) was orally administered to animals immediately after induction of diabetes and was continued for eight weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) remadynamic function. Myocardial oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD), the level of malondialdehyde (MDA) as well as heme oxygenase-1 (HO-1) protein level. Myocardial connective tissue growth factor (CTGF) level was measured by Western blot in all rats at the end of the study. In the untreated diabetic rats, left ventricular systolic pressure (LVSP) rate of pressure rose (+dp/dt), and rate of pressure decay (−dp/dt) were depressed while left ventricular end-diastolic pressure (LVEDP) was increased, which indicated the reduced left ventricular contractility and slowing of left ventricular relaxation. The level of SOD decreased, CTGF and HO-1 protein expression and MDA content rose. Riboflavin treatment significantly improved left ventricular systolic and diastolic function in diabetic rats, there were persistent increases in significant activation of SOD and the level of HO-1 protein, and a decrease in the level of CTGF. These results suggest that riboflavin treatment ameliorates myocardial function and improves heart oxidant status, whereas raising myocardial HO-1 and decreasing myocardial CTGF levels have beneficial effects on diabetic cardiomyopathy.
riboflavin; diabetic cardiomyopathy; heme oxygenase-1.
Budding of HIV-1 requires the binding of the PTAP late domain of the Gag p6 protein to the UEV domain of the TSG101 subunit of ESCRT-I. The normal function of this motif in cells is in receptor downregulation. Here we report the 1.4 to 1.6 Å structures of the human TSG101 UEV domain alone and with wild-type and mutant HIV-1 PTAP and Hrs PSAP nonapeptides. The hydroxyl of the Thr or Ser residue in the P(S/T)AP motif hydrogen bonds with the main-chain of Asn69. Mutation of the Asn to Pro, blocking the main-chain amide, abrogates PTAP motif binding in vitro and blocks budding of HIV-1 from cells. N69P and other PTAP binding-deficient alleles of TSG101 did not rescue HIV-1 budding. However, the mutant alleles did rescue downregulation of endogenous EGF receptor. This demonstrates that the PSAP motif is not rate determining in EGF receptor downregulation under normal conditions.
The aim of the study was to investigate the suppressive effects of pSilencer2.1-U6-siRNA-stat3 recombinant plasmids on the growth of ovarian cancer in vitro.
Material and methods.
Three pairs of DNA template (stat3-1, stat3-2, stat3-3) specific for different target sites on stat3 mRNA were synthesized to reconstruct pSilencer2.1-U6-siRNA-stat3s, which were transfected into SKOV3 cells. The expressions of STAT3, BcL-2, cyclin D1 and C-myc in these cells were detected by Western blot and Northern blot. The cell cycle and the growth were determined by flow cytometry (FCM) and MTT assay, respectively. Cell apoptosis was determined by TUNEL staining.
Of the three siRNAs, only siRNA targeting stat3-3 markedly suppressed the protein expression of stat3 in SKOV3 cells; MTT assay and FCM showed that transfection of stat3-3 siRNA could significantly suppress the growth of SKOV3 cells and arrest the cell cycle in vitro. TUNEL staining also showed massive apoptosis in SKOV3 cells transfected with stat3-3 siRNA.
pSilencer2.1-U6-siRNA-stat3-3 can significantly inhibit the STAT3 expression in human ovarian cancer cells resulting in the inhibition of the cancer growth and the increase of apoptosis of cancer cells.
RNA interference; stat3; SKOV3 cells; ovarian cancer; apoptosis
AIM: To summarize clinical, endoscopic, radiologic and pathologic features of special diaphragm-like strictures found in small bowel, with no patient use of non-steroidal anti-inflammatory drugs (NSAIDs).
METHODS: From January 2000 to December 2009, 5 cases (2 men and 3 women, with a mean age of 41.6 years) were diagnosed as having diaphragm-like strictures of small bowel on imaging, operation and pathology. All the patients denied the use of NSAIDs. The clinical, endoscopic, radiologic and pathologic findings in these 5 patients were retrospectively reviewed from the hospital database. Images of capsule endoscopy (CE) and small bowel follow-through (SBFT) obtained in 3 and 3 patients, respectively, and images of double-balloon enteroscopy and computed tomography enterography (CTE) obtained in all 5 patients were available for review.
RESULTS: All patients presented with long-term (2-16 years) symptoms of gastrointestinal bleeding and varying degrees of anemia. There was only one stricture in four cases and three lesions in one case, and all the lesions were located in the middle or distal segment of ileum. Circumferential stricture was shown in the small bowel in three cases in the CE image, but the capsule was retained in the small bowel of 2 patients. Routine abdomen computed tomography scan showed no other abnormal results except gallstones in one patient. The lesions were shown as circumferential strictures accompanied by dilated small bowel loops in the small bowel on the images of CTE (in all 5 cases), SBFT (in 2 cases) and double-balloon enteroscopy (in all cases). On microscopy, a chronic inflammatory infiltrate and circumferential diaphragm were found in all lesions.
CONCLUSION: Diaphragm-like strictures of small bowel might be a special consequence of unclear damaging insults to the intestine, having similar clinical, endoscopic, radiologic and pathologic features.
Small bowel; Gastrointestinal bleeding; Diaphragm; Stricture; Endoscopy; Computed tomography; Enterography
Alterations in protein composition and oxidative damage of high-density lipoprotein (HDL) have been proposed to impair the cardioprotective properties of HDL. We tested whether relative levels of proteins in HDL2 could be used as biomarkers for coronary artery disease (CAD).
Twenty control and eighteen CAD subjects matched for HDL-cholesterol, age, and sex were studied. HDL2 isolated from plasma was digested with trypsin and analyzed by high-resolution matrix-assisted laser desorption ionization mass spectrometry (MALDI- MS) and pattern recognition analysis.
Partial least squares discriminant analysis (PLS-DA) of mass spectra clearly differentiated CAD from control subjects with area under the Receiver operating characteristic curve (ROCAUC) 0.94. Targeted tandem mass spectrometric analysis of the model's significant features revealed that HDL2 of CAD subjects contained oxidized methionine residues of apolipoprotein A-I and elevated levels of apolipoprotein C-III. A proteomic signature composed of MALDI-MS signals from apoA-I, apoC-III, Lp(a) and apoC-I accurately classified CAD and control subjects (ROCAUC = 0.82).
HDL2 of CAD subjects carries a distinct protein cargo and that protein oxidation helps generate dysfunctional HDL. Moreover, models based on selected identified peptides in MALDI-TOF mass spectra of the HDL may have diagnostic potential.
Cardiovascular risk score; inflammation; mass spectrometry; oxidized HDL; partial least squares discriminant analysis
A porous poly(L-lactic acid)/β-tricalcium phosphate (PLLA/β-TCP) composite scaffold was fabricated using a novel technique comprising powder mixing, compression molding, low-temperature treatment, and particulate leaching without any organic solvent. The effect of this scaffold on osteoblast proliferation and differentiation was evaluated in vitro. The fabricated scaffold had a homogeneously interconnected porous structure with a porosity of 70% and compressive strength of 1.35 MPa. The methylthiazol tetrazolium values and alkaline phosphatase (ALP) activity of osteoblasts seeded on the solvent-free scaffold were significant higher than those of the control. Using real-time PCR, gene expressions of ALP, osteocalcin, and type 1 collagen were shown to be upregulated. As the method does not use any organic solvent, it eliminates problems associated with organic solvent residue and therefore improves the cell compatibility. It has a promising potential for the preparation of porous scaffold for bone tissue engineering.
biocompatibility; biomaterials; composites; poly(L-lactic acid); β-tricalcium phosphate
Diabetic nephropathy is a long-term complication of diabetic mellitus. Many experimental evidences suggest that persistent hyperglycaemia generates intracellular reactive oxygen species (ROS) and upregulates transforming growth factor-b1 and extracellular matrix expression in mesangial and tubular epithelial cells, which is involved of free radicals in the pathogenesis of diabetes and more importantly in the development of diabetic complications. Antioxidants effectively inhibit high-glucose- and H2O2-induced transforming growth factor-b1 and fibronectin upregulation, thus providing evidence that ROS play an important role in high glucose-induced renal injury. The flavonoid luteolin has been shown to possess direct antioxidant activity, therefore we hypothesize that it may be useful in treatment of many chronic disease associated with oxidative stress, such as diabetic nephropathy via its antioxidant properties. Our results suggested that protection against development of diabetic nephropathy by luteolin treatment involved changes in superoxide dismutase (SOD) activity, the malondialdehyde (MDA) content and expression of Heme Oxygenase-1 (HO-1) protein.
Diseases of the kidneys and genitourinary tract are common health problems that affect people of all ages and demographic backgrounds. In this study, we compared the quantity and quality of nephrological and urological articles published in international journals from the three major regions of China: the mainland (ML), Hong Kong (HK), and Taiwan (TW).
Nephrological and urological articles originating from ML, TW, and HK that were published in 61 journals from 1999–2008 were retrieved from the PubMed database. We recorded the numbers of total articles, clinical trials, randomized controlled trials, case reports, impact factors (IF), citations, and articles published in the leading general-medicine journals. We used these data to compare the quantity and quality of publication output from the three regions.
The total number of articles increased significantly from 1999 to 2008 in the three regions. The number of articles from ML has exceeded that from HK since 2004, and surpassed that from TW in 2008. Publications from TW had the highest accumulated IF, total citations of articles, and the most articles published in leading general-medicine journals. However, HK publications had the highest average IF. Although ML produced the largest quantity of articles, it exhibited the lowest quality among the three regions.
The number of nephrological and urological publications originating from the three major regions of China increased significantly from 1999 to 2008. The annual number of publications by ML researchers exceeded those from TW and HK. However, the quality of articles from TW and HK was higher than that from ML.
We examined the impact of metabolic syndrome (MS) on coronary stenosis progression and major cardiovascular (CV) events and investigated the mitigating effects of low-density lipoprotein cholesterol (LDL-C) lowering and LDL-C-lowering plus high-density lipoprotein cholesterol (HDL-C) raising. This analysis combined individual patient data from 445 subjects who participated in 3 double-blinded, randomized, placebo-controlled trials (FATS, HATS, and AFREGS) comparing intensive lipid therapy to placebos on coronary stenosis progression by quantitative coronary angiography and on major CV events. The primary endpoints were the change in mean proximal coronary diameter stenosis (Δ%Sprox) over 3 years and the frequency of the pre-defined composite of coronary artery disease (CAD) death, nonfatal myocardial infarction (MI), stroke and revascularization due to worsening ischemia. Patients with the MS had 50% more rapid coronary stenosis progression and 64% increased CV event frequency compared to those without. More rapid coronary stenosis progression was significantly and independently associated with 3.5-fold increased event risk (p<0.001). Combination lipid therapy significantly decreased stenosis progression by 83% (Δ%Sprox=0.5 vs. 2.9, p<0.001) in patients with MS, and induced a small net regression in those without (Δ%Sprox=−0.3 vs. 2.0, p<0.001). Combination therapy reduced the event rate by 54% (13 vs. 28%, p=0.03) in those with MS and by 82% (3 vs. 17%, p=0.002) without. On average, each 10% reduction in LDL-C or 10% increase in HDL-C was significantly associated with 0.3 Δ%Sprox reduction. Each 10% LDL-C-lowering or 10% HDL-C-raising was associated with 11% (p=0.02) or 22% (p<0.001) event risk reduction. In conclusion, patients with MS have significantly more rapid coronary stenosis progression and a higher frequency of CV events. Greater stenosis progression rate is associated with a higher event rate. LDL-C-lowering and HDL-C-raising therapies independently and significantly decrease coronary stenosis progression and reduce CV events.
metabolic syndrome; coronary artery disease; cardiovascular events; lipid therapy
Direct in vivo investigation of human metabolism is complicated by the distinct metabolic functions of various sub-cellular organelles. Diverse micro-environments in different organelles may lead to distinct functions of the same protein and the use of different enzymes for the same metabolic reaction. To better understand the complexity in the human metabolism, a compartmentalized human metabolic network with integrated sub-cellular location information is required.
We extended the previously reconstructed Edinburgh Human Metabolic Network (EHMN) [Ma, et al. Molecular Systems Biology, 3:135, 2007] by integrating the sub-cellular location information for the reactions, adding transport reactions and refining the protein-reaction relationships based on the location information. Firstly, protein location information was obtained from Gene Ontology and complemented by a Swiss-Prot location keywords search. Then all the reactions in EHMN were assigned to a location based on the protein-reaction relationships to get a preliminary compartmentalized network. We investigated the localized sub-networks in each pathway to identify gaps and isolated reactions by connectivity analysis and refined the location information based on information from literature. As a result, location information for hundreds of reactions was revised and hundreds of incorrect protein-reaction relationships were corrected. Over 1400 transport reactions were added to link the location specific metabolic network. To validate the network, we have done pathway analysis to examine the capability of the network to synthesize or degrade certain key metabolites. Compared with a previously published human metabolic network (Human Recon 1), our network contains over 1000 more reactions assigned to clear cellular compartments.
By combining protein location information, network connectivity analysis and manual literature search, we have reconstructed a more complete compartmentalized human metabolic network. The whole network is available at http://www.ehmn.bioinformatics.ed.ac.uk and free for academic use.
Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione integrase inhibitors, we report differential effects on inhibitory potency induced by introduction of an α-chiral center into a key aryl substitutent. We show that introduction of the chiral center is uniformly deleterious to binding, with the (R)-enantiomer being more deleterious than the (S)-enantiomer. A greater enantiomeric difference in potency is shown by inhibitors that have restricted rotation of the aryl ring, with the larger difference being due to poorer potency of the (R)-enantiomer rather than higher potency of the (S)-enantiomer. The potency difference for enantiomers based on the isoindoline-1,3-dione ring system is less than for those derived from the isoindol-1-one ring system. Our findings provide useful information that should aid in understanding molecular binding interactions of DKA – derived IN inhibitors.
HIV-1 integrase; inhibit; enantiomer; arylamide; diketoacid
Using 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione based HIV-1 integrase inhibitors as display platforms, we undertook a thorough examination of the effects of modifying the halogen substituents on a key benzyl ring that is hypothesized to bind in a hydrophobic pocket of the integrase•DNA complex. Data from this study suggest that in general dihalo – substituted analogues have higher potency than monohalo – substituted compounds, but that further addition of halogens is not beneficial.
Background and Aims
Aluminium (Al) toxicity and phosphorus (P) deficiency often co-exist in acidic soils and limit crop production worldwide. Lespedeza bicolor is a leguminous forage species that grows very well in infertile, acidic soils. The objective of this study was to investigate the effects of Al and P interactions on growth of Lespedeza and the distributions of Al and P in two different Al-resistant species, and to explore whether P can ameliorate the toxic effect of Al in the two species.
Two species, Lespedeza bicolor and L. cuneata, were grown for 30 d with alternate Al and P treatments in a hydroponics system. Harvested roots were examined using a root-system scanner, and the contents of Al, P and other nutrient elements in the plants were determined using inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Haematoxylin staining was used to observe the distribution of Al in the roots of seedlings. After pre-culture with or without P application, organic acids in the exudates of roots exposed to Al were held in an anion-exchange resin, eluted with 2 m HCl and then analysed using high-performance liquid chromatography (HPLC).
Lespedeza bicolor exhibited a stronger Al resistance than did L. cuneata; Al exclusion mechanisms may mainly be responsible for resistance. P application alleviated the toxic effect of Al on root growth in L. bicolor, while no obvious effects were observed in L. cuneata. Much less Al was accumulated in roots of L. bicolor than in L. cuneata after P application, and the P contents in both roots and shoots increased much more for L. bicolor than for L. cuneata. Lespedeza bicolor showed a higher P/Al ratio in roots and shoots than did L. cuneata. P application decreased the Al accumulation in root tips of L. bicolor but not in L. cuneata. The amount of Al-induced organic acid (citrate and malate) exudation from roots pre-cultured with P was much less than from roots without P application; no malate and citrate exudation was detected in L. cuneata.
P enhanced Al resistance in the Al-resistant L. bicolor species but not in the Al-sensitive L. cuneata under relatively high Al stress, although P in L. cuneata might also possess an alleviative potential. Enhancement of Al resistance by P in the resistant species might be associated with its more efficient P accumulation and translocation to shoots and greater Al exclusion from root tips after P application, but not with an increased exudation of organic acids from roots.
Lespedeza bicolor; L. cuneata; Al toxicity; Al resistance; root morphology; phosphorus