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Biomedical subjects

J Ren

Publications and source records attributed to J Ren.

At least 37 records · Page 2Linked to original sources
PubMed2005

High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogen-activated protein kinase activation and apoptosis.

High-fat diet intake often leads to obesity, insulin resistance and hypertension, which present a common and detrimental health problem. However, precise mechanism underlying tissue damage due to high-fat diet-induced obesity has not been carefully elucidated. The present study was designed to examine the effect of high-fat diet intake on visceral advanced glycation end products (AGEs) formation, nuclear O-Glc-NAc modification and apoptosis in heart, liver and kidney. Adult male Sprague-Dawley weight-matched rats were fed for 12 weeks with a high-fat diet (45% kcal from fat) or an isocaloric low-fat diet (10% kcal from fat). High-fat diet feeding significantly elevated body weight. Blood pressure and heart rate were comparable between the two rat groups. Competitive enzyme-linked immunosorbent assay showed significantly elevated serum AGE levels, visceral AGE formation, caspase-3 activation and cytoplasmic DNA fragmentation in heart and liver but not kidney samples of high-fat diet fed rats compared with those from low-fat diet fed group. Western blot analysis further revealed that high-fat diet feeding induced overt nuclear O-Glc-NAc modification and p38 mitogen-activated protein kinase activation in heart and liver although not in kidney samples of the high-fat diet-fed rats. Collectively, our results indicated that high-fat diet intake is associated with obesity accompanied by elevated serum and visceral AGEs, visceral post-translational nuclear O-Glc-NAcylated modification and apoptosis, which may contribute to high-fat diet-induced tissue damage.

Acetylglucosaminidase↗
PubMed2004

Comparison of ligand-induced conformational changes and domain closure mechanisms, between prokaryotic and eukaryotic dehydroquinate synthases.

Dehydroquinate synthase (DHQS) is a potential target for the development of novel broad-spectrum antimicrobial drugs, active against both prokaryotes and lower eukaryotes. Structures have been reported for Aspergillus nidulans DHQS (AnDHQS) in complexes with a range of ligands. Analysis of these AnDHQS structures showed that a large-scale domain movement occurs during the normal catalytic cycle, with a complex series of structural elements propagating substrate binding-induced conformational changes away from the active site to distal locations. Compared to corresponding fungal enzymes, DHQS from bacterial species are both mono-functional and significantly smaller. We have therefore determined the structure of Staphylococcus aureus DHQS (SaDHQS) in five liganded states, allowing comparison of ligand-induced conformational changes and mechanisms of domain closure between fungal and bacterial enzymes. This comparative analysis shows that substrate binding initiates a large-scale domain closure in both species' DHQS and that the active site stereochemistry, of the catalytically competent closed-form enzyme thus produced, is also highly conserved. However, comparison of AnDHQS and SaDHQS open-form structures, and analysis of the putative dynamic processes by which the transition to the closed-form states are made, shows a far lower degree of similarity, indicating a significant structural divergence. As a result, both the nature of the propagation of conformational change and the mechanical systems involved in this propagation are quite different between the DHQSs from the two species.

Amino Acid Sequence↗
PubMed2004

Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors.

Leu100Ile, Val106Ala and Val108Ile are mutations in HIV-1 reverse transcriptase (RT) that are observed in the clinic and give rise to resistance to certain non-nucleoside inhibitors (NNRTIs) including the first-generation drug nevirapine. In order to investigate structural mechanisms of resistance for different NNRTI classes we have determined six crystal structures of mutant RT-inhibitor complexes. Val108 does not have direct contact with nevirapine in wild-type RT and in the RT(Val108Ile) complex the biggest change observed is at the distally positioned Tyr181 which is > 8 A from the mutation site. Thus in contrast to most NNRTI resistance mutations RT(Val108Ile) appears to act via an indirect mechanism which in this case is through alterations of the ring stacking interactions of the drug particularly with Tyr181. Shifts in side-chain and inhibitor positions compared to wild-type RT are observed in complexes of nevirapine and the second-generation NNRTI UC-781 with RT(Leu100Ile) and RT(Val106Ala), leading to perturbations in inhibitor contacts with Tyr181 and Tyr188. Such perturbations are likely to be a factor contributing to the greater loss of binding for nevirapine compared to UC-781 as, in the former case, a larger proportion of binding energy is derived from aromatic ring stacking of the inhibitor with the tyrosine side-chains. The differing resistance profiles of first and second generation NNRTIs for other drug resistance mutations in RT may also be in part due to this indirect mechanism.

Anti-HIV Agents↗
PubMed2004

Presynaptic modulation of cholinergic and non-cholinergic fast synaptic transmission in the myenteric plexus of guinea pig ileum.

Abstract These studies investigated receptors modulating release of mediators of fast excitatory postsynaptic potentials (fEPSPs) in guinea pig ileum myenteric plexus using electrophysiological methods. Fast EPSPs inhibited by >95% by hexamethonium (100 micromol L(-1)) were cholinergic; mixed fEPSPs were inhibited <95% by hexamethonium. Non-cholinergic fEPSPs were studied in the presence of hexamethonium. The alpha2-adrenergic receptor agonist UK 14304 inhibited cholinergic (maximum inhibition = 76%, EC(50) = 18 nmol L(-1)), mixed (81%, 21 nmol L(-1)) and non-cholinergic (76%, 44 nmol L(-1)) fEPSPs equally. The 5-HT(1) receptor agonist 5-carboxamidotryptamine inhibited cholinergic, mixed and non-cholinergic fEPSPs equally. Renzapride, increased non-cholinergic (33%) less than mixed (97%, 13 micromol L(-1)) fEPSPs. Renzapride inhibited the purely cholinergic fEPSPs (-29%) but potentiated the cholinergic component of mixed fEPSPs (39%). Prucalopride potentiated all fEPSPs equally (30-33%). 5-HT (0.1 micromol L(-1)) induced potentiation of cholinergic (75%), mixed (97%) and non-cholinergic (84%) fEPSPs was not statistically different. The potentiating effects of renzapride and 5-HT on fEPSPs were inhibited by the 5-HT(4) receptor antagonist, SB 204070 (10 nmol L(-1)). Renzapride (0.3 micromol L(-1)) blocked 5-HT-induced increases in cholinergic fEPSPs. alpha2-Adrenergic and 5-HT(1) receptors mediate inhibition of transmitter release from cholinergic and mixed terminals. 5-HT and prucalopride, acting at 5-HT(4) receptors, facilitate all fEPSPs; renzapride facilitates the cholinergic and non-cholinergic components of mixed fEPSPs but not purely cholinergic fEPSPs. Cholinergic synapses may express few 5-HT(4) receptors or a renzapride-insensitive 5-HT(4) receptor isoform.

Acetylcholine↗
PubMed2004

Transgenic overexpression of insulin-like growth factor I prevents streptozotocin-induced cardiac contractile dysfunction and beta-adrenergic response in ventricular myocytes.

Diabetic cardiomyopathy is characterized by cardiac dysfunction and altered level/function of insulin-like growth factor I (IGF-I). Both endogenous and exogenous IGF-I have been shown to effectively alleviate diabetes-induced cardiac dysfunction and oxidative stress. This study was designed to examine the effect of cardiac overexpression of IGF-I on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse myocytes. Both IGF-I heterozygous transgenic mice and their wild-type FVB littermates were made diabetic with a single injection of STZ (200 mg/kg, i.p.) and maintained for 2 weeks. The following mechanical indices were evaluated in ventricular myocytes: peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Intracellular Ca2+ was evaluated as resting and peak intracellular Ca2+ levels, Ca2+-induced Ca2+ release and intracellular Ca2+ decay rate (tau). STZ led to hyperglycemia in FVB and IGF-I mice. STZ treatment prolonged TPS and TR90, reduced Ca2+-induced Ca2+ release, increased resting intracellular Ca2+ levels and slowed tau associated with normal PS and +/- dL/dt. All of which, except the elevated resting intracellular Ca2+, were prevented by the IGF-I transgene. In addition, myocytes from STZ-treated FVB mice displayed an attenuated contractile response to the beta-adrenergic agonist isoproterenol, which was restored by the IGF-I transgene. Contractile response to the alpha-adrenergic agonist phenylephrine and angiotensin II was not affected by either STZ treatment or IGF-I. These results validate the beneficial role of IGF-I in diabetic cardiomyopathy, possibly due to an improved beta-adrenergic response.

Adrenergic alpha-Agonists↗
PubMed2004

Leptin and hyperleptinemia - from friend to foe for cardiovascular function.

The obese gene product, leptin, plays a central role in food intake and energy metabolism. The physiological roles of leptin in human bodily function have been broadened over the past decade since leptin was first discovered in 1994. Evidence has suggested that leptin plays a specific role in the intricate cascade of cardiovascular events, in addition to its well-established metabolic effects. Leptin, a hormone linking adiposity and central nervous circuits to reduce appetite and enhance energy expenditure, has been shown to increase overall sympathetic nerve activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin is capable of regulating cardiac and vascular contractility through a local nitric oxide-dependent mechanism. However, elevated plasma leptin levels or hyperleptinemia, have been demonstrated to correlate with hyperphagia, insulin resistance and other markers of the metabolic syndrome including obesity, hyperlipidemia and hypertension, independent of total adiposity. Elevated plasma leptin levels may be an independent risk factor for the development of cardiovascular disease. Although mechanisms leading to hyperleptinemia have not been well described, factors such as increased food intake and insulin resistance have been shown to rapidly enhance plasma leptin levels and subsequently tissue leptin resistance. These findings have prompted the speculation that leptin in the physiological range may serve as a physiological regulator of cardiovascular function whereas elevated plasma leptin levels may act as a pathophysiological trigger and/or marker for cardiovascular diseases due to tissue leptin resistance.

Appetite Regulation↗
PubMed2004

Stachyose extract from Rehmannia glutinosa Libosch. to lower plasma glucose in normal and diabetic rats by oral administration.

The hypoglycemic effects of water extract and stachyose extract (Part III) from Rehmannia glutinosa Libosch. were investigated in this paper by oral administration to normal, glucose- and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats. The results showed that Part III had the effect of lowering fasted plasma glucose level and partially preventing hyperglycemia induced by glucose (2.5 g x kg(-1), i.p.) and adrenaline (300 microg x kg(-1), i.p.), respectively, but no obvious dose-dependent effect was found when it was administered at the doses of 100, 200 and 400 mg x kg(-1) for 6 days, i.g. In alloxan-induced diabetic rats, Part III (200 mg x kg(-1) for 15 days, i.g.) gave a significant decrease in blood glucose level. The results suggested that Part III, which is mainly composed of stachyose from Rehmannia glutinosa Libosch., had a significant hypoglycemic effect in glucose- and adrenaline-induced hyperglycemic and alloxan-induced diabetic rats.

Administration, Oral↗
PubMed2003

Role of nitric oxide, tetrahydrobiopterin and peroxynitrite in glucose toxicity-associated contractile dysfunction in ventricular myocytes.

AIMS/HYPOTHESIS: Local overproduction of nitric oxide is seen in early stages of diabetes, which can react with superoxide (O(2)(-)) to form peroxynitrite (ONOO(-)). The aim of this study was to examine the effect of scavengers for nitric oxide, O(2)(-), ONOO(-) and NOS cofactor tetrahydrobiopterin (BH(4)) on high glucose-induced cardiac contractile dysfunction. METHODS: Ventricular myocytes were cultured for 24 h with either normal (N, 5.5 mmol/l) or high (25.5 mmol/l) glucose, with or without the nitric oxide scavengers haemoglobin (100 nmol/l), PTIO (100 micromol/l), the NOS inhibitor L-NMMA (100 micromol/l), superoxide dismutase (SOD, 500 U/ml), the ONOO(-) scavengers urate (100 micromol/l), MnTABP (100 micromol/l), BH(4) (10 micromol/l) and its inactive analogue NH(4) (10 micromol/l), and the GTP cyclohydrolase I inhibitor DAHP (1 mmol/l). Myocyte mechanics, NOS protein expression and activity were evaluated. RESULTS: High glucose myocytes showed reduced peak shortening, decreased maximal velocity of shortening/relengthening (+/- dL/dt), prolonged relengthening (TR(90)) and normal shortening duration (TPS) associated with reduced cytosolic Ca(2+) rise compared to normal myocytes. The high glucose-induced abnormalities were abrogated or attenuated by urate, MnTBAP, L-NMMA, BH(4), and SOD, whereas unaffected by haemoglobin, PTIO and NH(4). L-NMMA reduced peak shortening while PTIO and DAHP depressed +/- dL/dt and prolonged TPS or TR(90) in normal myocytes. High glucose increased NOS activity, protein expression of eNOS but not iNOS, which were attenuated by L-NMMA and BH(4), respectively. CONCLUSION/INTERPRETATION: These results suggested that NOS cofactor, NO and ONOO(-) play a role in glucose-induced cardiomyocyte contractile dysfunction and in the pathogenesis of diabetic cardiomyopathy.

Animals↗
PubMed2003

Partial genome sequencing of Rhodococcus equi ATCC 33701.

Preliminary analysis of a partial (30% coverage) genome sequence of Rhodococcus equi has revealed a number of important features. The most notable was the extent of the homology of genes identified with those of Mycobacterium tuberculosis. The similarities in the proportion of genes devoted to fatty acid degradation and to lipid biosynthesis was a striking but not surprising finding given the relatedness of these organisms and their success as intracellular pathogens. The rapid recent improvement in understanding of virulence in M. tuberculosis and other pathogenic mycobacteria has identified a large number of genes of putative or proven importance in virulence, homologs of many of which were also identified in R. equi. Although R. equi appears to have currently unique genes, and has important differences, its similarity to M. tuberculosis supports the need to understand the basis of virulence in this organism. The partial genome sequence will be a resource for workers interested in R. equi until such time as a full genome sequence has been characterized.

Aerobiosis↗
PubMed2003

Slow excitatory synaptic transmission mediated by P2Y1 receptors in the guinea-pig enteric nervous system.

Electrophysiological recording was used to study a type of slow excitatory postsynaptic potential (slow EPSP) that was mediated by release of ATP and its action at P2Y1 receptors on morphologically identified neurones in the submucosal plexus of guinea-pig small intestine. MRS2179, a selective P2Y1 purinergic receptor antagonist, blocked both the slow EPSP and mimicry of the EPSP by exogenously applied ATP. Increased conductance accounted for the depolarization phase of the EPSP, which occurred exclusively in neurones with S-type electrophysiological behaviour and uniaxonal morphology. The purinergic excitatory input to the submucosal neurones came from neighbouring neurones in the same plexus, from neurones in the myenteric plexus and from sympathetic postganglionic neurones. ATP-mediated EPSPs occurred coincident with fast nicotinic synaptic potentials evoked by the myenteric projections and with noradrenergic IPSPs evoked by sympathetic fibres that innervated the same neurones. The P2Y1 receptor on the neurones was identified as a metabotropic receptor linked to activation of phospholipase C, synthesis of inositol 1,4,5-trisphosphate and mobilization of Ca2+ from intracellular stores.

Adenosine Diphosphate↗
PubMed2003

Ligand-induced conformational changes and a mechanism for domain closure in Aspergillus nidulans dehydroquinate synthase.

In order to investigate systematically substrate and cofactor-induced conformational changes in the enzyme dehydroquinate synthase (DHQS), eight structures representing a series of differently liganded states have been determined in a total of six crystal forms. DHQS in the absence of the substrate analogue carbaphosphonate, either unliganded or in the presence of NAD or ADP, is in an open form where a relative rotation of 11-13 degrees between N and C-terminal domains occurs. Analysis of torsion angle difference plots between sets of structures reveals eight rearrangements that appear relevant to domain closure and a further six related to crystal packing. Overlapping 21 different copies of the individual N and C-terminal DHQS domains further reveals a series of pivot points about which these movements occur and illustrates the way in which widely separated secondary structure elements are mechanically inter-linked to form "composite elements", which propagate structural changes across large distances. This analysis has provided insight into the basis of DHQS ligand-initiated domain closure and gives rise to the proposal of an ordered sequence of events involving substrate binding, and local rearrangements within the active site that are propagated to the hinge regions, leading to closure of the active-site cleft.

Adenosine Diphosphate↗
PubMed2003

Long-term effects of fertilization on soil organic carbon changes in continuous corn of northeast China: RothC model simulations.

Soil organic C (SOC) content can increase by managing land use practices in which the rates of organic C input exceed those of organic C mineralization. Understanding the changes in SOC content of Black soils (mainly Typic Halpudoll) in northeast China is necessary for sustainable using of soil resources there. We used the RothC model to estimate SOC levels of Black soils under monoculture cropping corn in a long-term fertilization trial at Gongzhuling, Jilin Province, China. The model outputs for the changes in SOC were compared with measured data in this long-term fertilization/manure trial. The sound performance of model in simulating SOC changes suggests that RothC is feasible with Black soils in the temperate climatic region of northeast China. The modeled and measured results indicated that the treatment without fertilizer/farmyard manure (FYM) addition led to a continuous decline in SOC during the study period and N and NPK fertilization were inadequate to maintain the SOC levels in the plow layer (upper 20 cm) unless FYM was added under the current conventional management associated with no above-ground crop residues returning into the soil. Soil organic carbon could follow the same path of decline if the same management practices are maintained. Model results indicate that returning above-ground crop residues to the soil from 2002 to 2022 would increase SOC by 26% for the treatment without fertilization addition, 40% for N treatment, 45% for NPK treatment, and 38% and 46% for N and NPK treatments with FYM addition, compared to the levels in the corresponding treatments in 2002. The simulation results suggest that the RothC model is a feasible tool to assess SOC trend under different management practices, and returning above-ground crop residues into the soil would lead to a remarkable increase in SOC of Black soils in the region.

Agriculture↗
PubMed2003

Insulin-like growth factor I (IGF-1) supplementation prevents diabetes-induced alterations in coenzymes Q9 and Q10.

Diabetes, which causes enhanced oxidative stress, is a multifactorial disease that leads to deleterious effects in many organ systems within the body. Ubiquinones (coenzyme Q(9) and Q(10)) are amphipathic molecular components of the electron transport chain that function also as endogenous antioxidants and attenuate the diabetes-induced decreases in antioxidant defense mechanisms. Insulin-like growth factor 1 (IGF-1) is considered to be an "essential surviving factor", the level and function of which are compromised in diabetes. This study investigated the impact of IGF-1 supplementation on ubiquinone levels in a rat model of type I diabetes. Adult male Sprague-Dawley rats were divided into four groups: control, control plus IGF-1, diabetic and diabetic plus IGF-1. Diabetic animals received a single intravenous injection of streptozotocin (STZ, 55 mg/kg). IGF-1 supplementation groups received a daily intraperitoneal dose of 3 mg IGF-1 per kilogram body weight for 7 weeks. Coenzyme Q(9) and Q(10) levels were assessed by ultraviolet detection on high pressure liquid chromatography. STZ caused a significant reduction in body weight and an elevation in blood glucose level, which were not prevented by IGF-1 supplementation. In addition Q(9) and Q(10) levels in diabetic liver were significantly elevated. IGF-1 supplementation prevented liver alterations in Q(10) but not Q(9) levels. Q(9) and Q(10) levels in diabetic kidney were significantly depressed, and these deleterious effects were abolished by IGF-1 treatment. These data suggest that IGF-1 antagonizes the diabetes-induced alterations in endogenous antioxidants including coenzyme Q(10), and hence may have a therapeutic role in diabetes.

Animals↗
PubMed2003

Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes.

Insulin resistance is a metabolic syndrome commonly seen in obesity. Leptin, the obese gene product, plays a role in the regulation of cardiac function. Elevated leptin levels have been demonstrated under insulin-resistant states such as obesity and hypertension, although their role in cardiac dysfunction is unknown. This study was designed to determine the impact of prediabetic insulin resistance on leptin levels and leptin-induced cardiac contractile response. Whole-body insulin resistance was generated with a 10-week dietary sucrose feeding. Contractile and intracellular Ca(2+) properties were evaluated in ventricular myocytes using an IonOptix system. The contractile indices analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), fura-fluorescence intensity change (deltaFFI) and decay rate (tau). Sucrose-fed rats displayed significantly elevated body weight and plasma leptin levels, depressed PS, +/-dL/dt, shortened TPS, prolonged TR(90) and tau, as well as reduced deltaFFI compared to the starch-fed control group. Leptin (1-1000 nM) elicited a concentration-dependent depression of PS and deltaFFI in myocytes from both starch and sucrose groups. Leptin-induced contractile depression was abolished by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyle ester, elevation of the extracellular Ca(2+) concentration, the Janus activated kinase 2 inhibitor AG-490 or the mitogen activated protein kinase inhibitor SB203580 in myocytes from both sucrose and starch groups. Moreover, AG-490 and SB203580 unmasked a positive response of PS in myocytes from both groups. These data indicate that insulin resistance directly induces hyperleptinemia and cardiac contractile dysfunction, without affecting leptin-mediated cardiac contractile function at the myocyte level.

Animals↗
PubMed2003

Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients.

BACKGROUND: Chronic fatigue syndrome (CFS) is an increasing medical phenomenon of unknown aetiology leading to high levels of chronic morbidity. Of the many hypotheses that purport to explain this disease, immune system activation, as a central feature, has remained prominent but unsubstantiated. Supporting this, a number of important cytokines have previously been shown to be over-expressed in disease subjects. The diagnosis of CFS is highly problematic since no biological markers specific to this disease have been identified. The discovery of genes relating to this condition is an important goal in seeking to correctly categorize and understand this complex syndrome. OBJECTIVE: The aim of this study was to screen for changes in gene expression in the lymphocytes of CFS patients. METHODS: 'Differential Display' is a method for comparing mRNA populations for the induction or suppression of genes. In this technique, mRNA populations from control and test subjects can be 'displayed' by gel electrophoresis and screened for differing banding patterns. These differences are indicative of altered gene expression between samples, and the genes that correspond to these bands can be cloned and identified. Differential display has been used to compare expression levels between four control subjects and seven CFS patients. RESULTS: Twelve short expressed sequence tags have been identified that were over-expressed in lymphocytes from CFS patients. Two of these correspond to cathepsin C and MAIL1 - genes known to be upregulated in activated lymphocytes. The expression level of seven of the differentially displayed sequences have been verified by quantifying relative level of these transcripts using TAQman quantitative PCR. CONCLUSION: Taken as a whole, the identification of novel gene tags up-regulated in CFS patients adds weight to the idea that CFS is a disease characterized by subtle changes in the immune system.

Expressed Sequence Tags↗
PubMed2003

Arteriogenesis: role of nitric oxide.

Arteriogenesis is an important process for adapting the pre-existing circuit of vessels into functional collateral conduits for delivery of oxygen enriched blood to tissue distal to occlusion of a large, peripheral conduit artery. Recent evidence has shown that arteriogenesis is regulated by nitric oxide (NO), angiogenic factors and shear stress. NO significantly impacts vasomotor tone to enhance conductance of the newly recruited collateral arteries, and this effect is augmented by exercise training prior to arterial occlusion. NO-mediated increases in vascular conductance allows for greater collateral dependent blood flow to the tissue distal to occlusion. NO production is also critical to the efficacy of therapeutic arteriogenesis achieved by delivery of exogenous angiogenic growth factors (VEGF, FGF-2) or by exercise training. The critical role of NO in therapeutic arteriogenesis is independent of NO-mediated changes in vascular conductance and implies a central role in arteriogenic signaling events. Maintenance, or improvement, of NO production and signaling, such as with regular exercise, may improve endothelial cell function and thus may help preserve the arteriogenic potential of preexisting collateral networks.

Animals↗