Effects of PPARg agonist pioglitazone on rat hepatic fibrosis

AIM:To investigate effects of pioglitazone on rat hepaticfibrosis and to explore its mechanism.METHODS:Rat hepatic fibrosis was induced by carbontetrachloride (CCl_4).Forty Sprague-Dawley rats were dividedrandomly into 4 groups:control,model,and two treatment(PⅠ,PⅡ) groups.Except for rats in control group,all ratswere given subcutaneous injection of 400 mL/L CCl_4,twicea wk for 8 wk.Rats in PⅠ and PⅡ groups were also treatedwith pioglitazone of 3 mg/kg,daily via gastrogavagebeginning on the 1~(st) day and at the end of the 2~(nd) week,administration of CCl_4 respectively.Liver functions (ALT,AST),serum fibrotic markers (HA,LN,PCⅣ) and hepatichydroxyproline (HP) concentration were determinedrespectively.Histochemical staining of formalin-fixed liversections with HE,Masson-Trichrome,and immunohistochemicalstaining for α-smooth muscle actin (α-SMA) were performed.Modified Knodell and Chevallier semi-quantitative scoringsystem (SSS) was used to evaluate necroinflammatoryactivity and fibrosis degree.RESULTS:Compared with model group,pioglitazonesignificantly reduced the serum levels of ALT,AST,HA,LNand PCⅢ (P<0.05 or <0.01).The HP concentrations in PⅠ(210.90±24.07 μg/g),and PⅡ (257.36±30.55 μg/g) groups werealso lower than those in model group (317.80±36.44 μg/g)(P<0.01).Histologic examination showed that PⅠ and PⅡgroups had milder hepatocellular degeneration,necrosisand infiltration of inflammatory cells,and thinner or lessfibrotic septa than did model group.The scores fornecroinflammation in PⅠ (2.80±1.03),and PⅡ (3.00±1.05)groups were significantly reduced as compared with modelgroup (4.88±2.30)(P<0.05 or <0.01);the fibrosis scoresin PⅠ(3.40±1.65),and PⅡ (4.60±1.35)groups were alsomarkedly lower than those in model group (7.00±3.21)(P<0.05 or <0.01).Immunohistochemical staining showedthat expression of α-SMA in PⅠ and PⅡ groups wasameliorated dramatically compared with model group.CONCLUSION:PPARγagonist pioglitazone greatly retardsthe progression of rat hepatic fibrosis induced by CCl_4through inhibition of HSC activation and amelioration ofhepatocyte necroinflammation in rats.     

Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic micro-environment?

OBJECTIVE: The objective of this study was to explore the relationship between low density lipoprotein (LDL) and dendritic cell (DC) activation, based upon the hypothesis that reactive oxygen species (ROS)-mediated modification of proteins that may be present in local DC microenvironments could be important as mediators of this activation. Although LDL are known to be oxidised in vivo, and taken up by macrophages during atherogenesis; their effect on DC has not been explored previously. METHODS: Human DCs were prepared from peripheral blood monocytes using GM-CSF and IL-4. Plasma LDLs were isolated by sequential gradient centrifugation, oxidised in CuSO(4), and oxidation arrested to yield mild, moderate and highly oxidised LDL forms. DCs exposed to these LDLs were investigated using combined phenotypic, functional (autologous T cell activation), morphological and viability assays. RESULTS: Highly-oxidised LDL increased DC HLA-DR, CD40 and CD86 expression, corroborated by increased DC-induced T cell proliferation. Both native and oxidised LDL induced prominent DC clustering. However, high concentrations of highly-oxidised LDL inhibited DC function, due to increased DC apoptosis. CONCLUSIONS: This study supports the hypothesis that oxidised LDL are capable of triggering the transition from sentinel to messenger DC. Furthermore, the DC clustering-activation-apoptosis sequence in the presence of different LDL forms is consistent with a regulatory DC role in immunopathogenesis of atheroma. A sequence of initial accumulation of DC, increasing LDL oxidation, and DC-induced T cell activation, may explain why local breach of tolerance can occur. Above a threshold level, however, supervening DC apoptosis limits this, contributing instead to the central plaque core.     

The therapeutic modulation of atherogenic dyslipidemia and inflammatory markers in the metabolic syndrome: what is the clinical relevance?

The metabolic syndrome consists of a constellation of clinical and biochemical risk factors that cluster together and heighten the risk for atherogenesis, cardiovascular diseases, and diabetes. Established risk cardiovascular factors like hypertension, atherogenic dyslipidaemia, and glucose intolerance occur in the setting of insulin resistance and central adiposity, with genetic and environmental influences modulating the ultimate risk. Chronic insults to the endothelium take its toll in the form of silent as well as clinically evident cardiovascular events. The cellular and vascular accompaniments have shed some light into the underlying pathophysiology. Heightened, low-grade inflammatory processes as well as a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis have been examined. In recent years there has been an explosion of basic and clinical knowledge related to the metabolic syndrome. Although dyslipidaemia is considered a traditional risk component for the syndrome, its qualitative aspects, genetically determined subfractions, and variation in proatherogenic tendency have generated renewed interest and debate. New targets within the dyslipidaemic spectrum that have differing clinical relevance are being evaluated. The effect of heredity, lifestyle changes, pharmacotherapeutic agents, and supplements is being investigated. Further research into the impact of dyslipidemia and inflammation as both pathophysiologic risk factors and objects for targeted therapy in the metabolic syndrome should deepen our understanding and unravel answers to the underlying dynamics in this global epidemic.     

Effects of the GLP-1 receptor agonist lixisenatide on postprandial glucose and gastric emptying – preclinical evidence

In addition to promoting glucose homeostasis, glucagon-like peptide 1 (GLP-1) has a number of extra-pancreatic effects that regulate appetite and body weight. GLP-1 delays gastric emptying, which is vital for postprandial glucose (PPG) control. As GLP-1 is rapidly degraded by protease dipeptidyl peptidase-4, a number of degradation-resistant GLP-1 receptor agonists (GLP-1RAs) have been developed for the treatment of Type 2 diabetes mellitus. These agents can be broadly categorized as being short- or long-acting, based on their pharmacokinetic profile. Short-acting agonists predominantly affect PPG and delay gastric emptying in a sustained manner, whereas long-acting agents largely affect fasting plasma glucose and their delay in gastric emptying appears to be subjected to tachyphylaxis. Lixisenatide is a “short-acting” once-daily prandial GLP-1RA. This review provides an overview of the preclinical studies that are currently available and that evaluate the efficacy of lixisenatide on gastric emptying and PPG levels. The preclinical evidence outlined in this review supports the efficacy of lixisenatide in reducing PPG excursions and delaying gastric emptying. Furthermore, in contrast to long-acting agents, the actions of lixisenatide do not appear to be subjected to tachyphylaxis.     

Effects of Exercise on the Flow of Blood and Lymph

One of the greatest benefits derived fromexerciser is the improved circulation of bloodand lymph to all parts of the body,whichitbrings about.The blood has several important functions,namely,(1) to absorb nutrient material fromthe intestine and distribute it throughout thebody,(2)to take oxygen from the lungs andconvey it to the tissues,(3)toremove wasteproducts from the tissues,and (4) to distri-bute and equalize body heat. To perform thesefunctions effectively the circulatory systemrequires the stimuli of muscular activity.Exercise causes the heart to beat more for     

Effects of α-tocopherol on platelets and the coagulation system

Vitamin E is one of the most widely used antioxidants in cryopreservation and preservation technology. The objective of this study is to examine the effect of vitamin E on platelets and the coagulation system. Vitamin E was added at different concentrations in the range between 0.25 and 5 mM to donor plasma. Using a STA/STA Compact coagulation analyzer the following clotting tests were performed: prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). The control clotting times PT (13.80 - 0.4 s), APTT (27.4 - 2.4 s) and TT (17.6 - 0.4 s) remained unchanged in the presence of vitamin E. The effect of vitamin E on platelets was assessed by platelet-induced clot retraction (PICR) and aggregation by thrombin. PICR was unaffected by vitamin E. Platelet aggregation, however, was profoundly inhibited by vitamin E. We found that inhibition of platelet aggregation by vitamin E was concentration dependent: increasing with increasing vitamin E concentration. This inhibitory effect, however, was widely reversible upon dilution of vitamin E with autologus platelet-poor plasma.     

Is insulin resistance atherogenic? A review of the evidence

Several factors that increase the risk of cardiovascular disease tend to cluster together in the same individual. Insulin resistance is believed to be a pathophysiological disturbance that underlies many of the risk factors. Whether insulin resistance per se is a cardiovascular risk factor is uncertain. Insulin resistance of myocardial muscle has been documented both in patients with type 2 diabetes and in nondiabetic subjects with angiographically proven coronary artery disease. In addition, in diabetic patients there is a mismatch between the redistribution of blood flow and glucose uptake during insulinization. Finally, the endothelial dysfunction and the hyperinsulinemia that accompany insulin resistance may adversely affect myocardial function. The evidence from epidemiological studies or clinical trials is, however, mixed. In at least one recent prospective study in patients with congestive heart failure, insulin resistance was an independent predictor of cardiac death. Conclusive proof would require a prospective study in which insulin resistance is measured directly and adequate account is taken of the classical cardiovascular risk factors.     

Identification of a μ-δ opioid receptor heteromer-biased agonist with antinociceptive activity

G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that G protein-coupled receptors, including opioid receptors, form dimers, and dimerization is necessary for receptor maturation, signaling, and trafficking. However, the physiological role of dimerization in vivo has not been well-explored because of the lack of tools to study these dimers in endogenous systems. To address this problem, we previously generated antibodies to μ-δ opioid receptor (μOR-δOR) dimers and used them to study the pharmacology and signaling by this heteromer. We also showed that the heteromer exhibits restricted distribution in the brain and that its abundance is increased in response to chronic morphine administration. Thus, the μOR-δOR heteromer represents a potentially unique target for the development of therapeutics to treat pain. Here, we report the identification of compounds targeting μOR-δOR heteromers through high-throughput screening of a small-molecule library. These compounds exhibit activity in μOR-δOR cells but not μOR or δOR cells alone. Among them, {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 was found to be a μOR-δOR–biased ligand, because its activity is blocked by the μOR-δOR heteromer antibody. Notably, systemic administration of {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 induced antinociceptive activity similar to morphine, and chronic administration of {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 resulted in lesser antinociceptive tolerance compared with morphine. Taken together, these results suggest that {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010, a μOR-δOR–biased ligand, could serve as a scaffold for the development of a unique type (heteromer-biased) of drug that is more potent and without the severe side effects associated with conventional clinical opioids.Studies with mice lacking opioid receptors show that the antinociceptive actions of clinically administered opioids, such as morphine or fentanyl, involve the activation of μ-opioid receptors (μORs) (1). However, continued opioid use leads to undesired side effects, including respiratory depression, constipation, immunosuppression, and development of tolerance and addiction (2). In an effort to identify novel compounds that are as effective as morphine in the treatment of chronic pain but without the associated side effects, our group, among others, has investigated the modulation of μOR function by receptor heteromerization. We found that μOR can form interacting complexes with δ-opioid receptors (δORs), that both receptors are in close proximity to interact in live cells, and that, in heterologous systems, low nonsignaling doses of some δOR ligands can potentiate the binding and signaling of μOR agonists (3–5). The recently reported crystal structure of μOR (6), in which receptors were crystallized as parallel dimers, is consistent with the idea that μOR can associate in complexes.We also generated mAbs selective to μOR-δOR heteromers; we showed that the latter can be detected in the brains of WT but not KO mice and that heteromer levels are increased in brain regions involved in pain processing after chronic morphine administration under a paradigm that leads to the development of tolerance (7). The idea that μOR-δOR heteromers may play a role in the development of tolerance to morphine is further supported by studies showing that genetic deletion of either δOR or β-arrestin or possible disruption of μOR-δOR heteromers leads to an enhancement of morphine-mediated antinociception and attenuation in the development of tolerance (8–10). Notably, we observed that a δOR antagonist, H-Tyr-Tic[CH2NH]-Phe-Phe-OH (TIPPψ), can potentiate morphine-mediated analgesia (4), and studies using bivalent ligands targeting μOR-δOR heteromers showed that these ligands induce antinociception with attenuated development of tolerance as well as conditioned place preference (11, 12). Taken together, these data suggest that occupancy of δOR by an antagonist could dissociate the antinociceptive effects of μOR agonists from the development of tolerance and addiction. Therefore, there is a need for ligands that selectively interact with μOR-δOR heteromers to understand their role in antinociception and development of tolerance to morphine.In an attempt to identify μOR-δOR heteromer-selective agonists, we used a β-arrestin recruitment assay and screened small molecules available through the Molecular Libraries Probe Production Centers Network. This screen identified 94 compounds that were biased to μOR-δOR heteromers compared with μOR, δOR, or serotonin 5HT_5A receptors. Among a dozen compounds that were repurchased and tested using secondary screens, one, which we named {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 [PubChem compound identifier (CID)23723457; Probe Report ID ML335], exhibited a strong μOR-δOR–biased activity that was blocked by μOR-δOR heteromer-selective mAb (μ-δ mAb). Furthermore, systemic administration of {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 led to antinociceptive activity similar to morphine but with a lower antinociceptive tolerance on chronic administration. Notably, although the intrathecal (i.t.) antinociceptive activity of {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 could be significantly blocked by i.t. administration of μ-δ mAb, the i.t. antinociceptive activity of morphine was not. These results suggest that {"type":"entrez-protein","attrs":{"text":"CYM51010","term_id":"993986068","term_text":"CYM51010"}}CYM51010 could serve as a scaffold for the development of unique therapeutics acting at the μOR-δOR heteromer for the effective management of pain.     

Effects of multidrug resistance, antisense RNA on the chemosensitivity of hepatocellular carcinoma cells

Introduction The overexpression of the multidrug resistance gene 1 (mdr1), a product of multidrug resistance multidrug resistance, is a major obstacle in cancer chemotherapy. Being a major P-glycoproteincancer chemotherapy. Being a major P-glycoprotein (P-gp), 17 kDa transmembrane protein acts as an energy-dependent drug efflux pump and keeps the concentration and efficacy intracellular anticancer drugs low.[1-4] Hepatocellular carcinoma (HCC) represents more than 5% of all cancers in the w…     

Effects of social relationships on mortality of the elderly: how do the influences change with the passage of time?

The purpose of this study was to determine the changes with time lapse in the influences of social relationship factors, in relation to mortality in the elderly. A baseline investigation was conducted in 1992 and survival conditions of 637 subjects aged 68-82 years were followed up for 12 years. The associations of social relationships with mortality were compared between the first and later half periods. The results showed that for men, close friends, group membership and finding life worth living were significantly associated with mortality in the first half period and the association disappeared in the later half; also in men, providing instrumental support was significantly associated in the 12-year period. In the first half, living arrangement was not significantly associated with mortality for men, and marital status and job were not for women, but in the later half, the association of those became apparent. The present study suggests that for men, the association of close friends, group membership and finding life worth living with mortality decreased with the passage of time while providing instrumental support had positive effects throughout the long term. The association of living arrangement increased for men, and marital status and job for women.     

Effects of aging on male fertility?

The increase in male life expectancy has raised issues concerning the impact of aging on the endocrine system and male fertility. This review focuses on the relationship of spermatogenesis to changes with age in androgen production and testicular morphology, the influence of age on semen parameters and chromosomal quality, and the impact of paternal age and pregnancy outcome.While age-related endocrine changes are well documented, those concerning semen parameters and consequent fertility are based on cross-sectional studies alone. Nevertheless, characteristic age-related morphological testicular alternations have been described, such as decreased numbers of Leydig cells paralleling decreased testosterone production, arteriosclerotic lesions, thickening and hernia-like protrusions of the basal membrane of the seminiferi tubules, and fibrotic thickening of the tunica albuginea. Surprisingly, these alterations do not lead to significant differences in sperm-morphology, time of spermatozoa development or sperm function between young and elderly males. Reports on decreased sperm motility, semen volume and changes in sperm count are contradictory. Although numerical chromosomal abnormalities of spermatozoa are not higher in aging males, an increase in structural aberrations can be observed. Consequently, children of elderly fathers show a 20% higher risk for autosomal dominant diseases, presumably due to increasing numbers of germ cell meioses and mitoses. Thus, the American Fertility Society recommends an age limit for semen donors of 50 years or less.     

Effects of Dangua recipe on myocardial ATP,PPAR-α,GLUT-4,and morphology in diabetic rats

<正>Objective To observe the effects of Dangua Recipe(DGR) on myocardial adenosine triphosphate (ATP),peroxisome proliferator-activated receptor-α(PPAR-α),glucose transporter type 4 (GLUT-4) and other related energy metabolism indicators and myocardial morphology in diabetic rats,and to provide reference for preventing     

Effect of PPAR γ agonist(rosiglitazone) on the secretion of Th2 cytokine in asthma mice

Objective: To explore the effect of PPAR γ agonist(rosiglitazone) on the secretion of Th2 cytokines and the proportion of immune cell subsets in asthma mice,Methods: Ovalbumin(OVA)-sensitized mice were used to build asthma models,Those mice were divided into the normal control group,model group and rosiglitazone group,Differences of the changes in lung histopathology of mice in the three group were observed through hematoxylin and eosin(HE) strain,and the numbers of the total cells,eosinophils and neutrophils in BALF of mice in the three groups were compared,ELISA and real-time PCR were employed to detect the protein levels of interleukin(IL)-5,IL-13,IL-4 and IL-10 and m RNA level,respectively,Flow cytometry number was implied to analyze the proportion of immune cell subsets in peripheral blood of mice,Results: Compared with the mice in the control group,and mice of the model group,the infiltration of inflammatory cells in BALF increased,bronchial smooth muscle became thickened,a large amount of collagen deposited,the secretion of Th2 cytokine increased significantly,the ratio of regulatory T cells(Treg) decreased,the ratio of T17 cells rose distinctly; while in mice of the rosiglitazone group,the changes of their lung histopathology were improved obviously,the number of infiltration of inflammatory cells declined,the thickened smooth muscle relieved,the deposition of collagen decreased,the secretion of Th2 cytokine was inhibited,the ratio of Treg went up,and the increased of the ratio of T17 cells was inhibited but still not return to normal level,Conclusions: Rosiglitazone can regulate the proportion of Treg and Th17 cells and inhibit the secretion of Th2 cytokines,which inhibit the airway inflammatory response for asthma mice effectively.     

Effects of γ-irradiation on the membrane ATPases of human erythrocytes from transfusional blood concentrates

Irradiation of blood derivatives is employed in blood banks to avoid transfusion-associated graft-vs-host disease. As irradiation can damage membranes and membrane proteins by generation of reactive oxygen species, we investigated whether the membrane permeability, Na⁺,K⁺–ATPase, and Ca²⁺–ATPase from red blood cell plasma membranes were altered by γ-irradiation. Whole blood was collected from healthy donors and concentrated to 90% cell fraction. Within 24 h of collection, blood concentrates were irradiated with 25 Gy of γ-radiation. At days 1, 7, 14, and 28 post-irradiation, fractions were removed and centrifuged. Na⁺,K⁺–ATPase and Ca²⁺–ATPase activities from ghost membranes were assessed by γ-³²P-ATP hydrolysis. The Na⁺,K⁺–ATPase was not immediately affected by irradiation, but it was inhibited by 40% by day 14 and until day 28. The Ca²⁺–ATPase was unaltered by irradiation. The rate and the maximal ⁴⁵Ca²⁺ uptake from re-sealed inside–out vesicles were reduced, and the passive efflux of ⁴⁵Ca²⁺ was increased. Thus, irradiation of blood concentrates increased the plasma membrane permeability to monovalent and divalent cations and would change ion homeostasis and cell function. We recommend the use of irradiated blood within a period shorter than 14 days after irradiation.     

Effects of Astragalus Membranaceus on oxygen consumption of intestine

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Effects of Nω-Nitro-l-Arginine and N-Acetyl-l-Cysteine on the Reversal of One-Kidney,One-Clip Hypertension

The present study evaluated whether nitric oxide (NO) synthesis blockade or potentiation (with N^ω-nitro-l-arginine or N-acetyl-l-cysteine, respectively) modulates the systemic and renal responses to unclipping in anesthetized one-kidney, one-clip hypertensive rats (1K-1C). Cardiac output was measured by thermodilution. In time-control rats, mean arterial pressure (MAP) decreased from 197 ± 8 mm Hg to 139 ± 4 mm Hg 3 h after unclipping, and cardiac index (CI) decreased by 35%, with a transient rise in sodium and water excretion and no changes in total peripheral resistance (TPR), glomerular filtration rate (GFR), or renal plasma flow (RPF). Administration of N^ω-nitro-l-arginine methyl ester (NAME, 10 μg/kg/min) blunted the hypotensive (from 190 ± 6 mm Hg to 157 ± 3 mm Hg), diuretic and natriuretic responses and potentiated the decrease in CI (40%) observed after unclipping, whereas TPR increased by 103%. Also, in rats given NAME, GFR and RPF decreased by 20% and 45%, respectively, at the end of the experiment. The effect of N-acetyl-l-cysteine (NAC, 300 mg/kg), a sulfhydryl group donor that may protect NO from free radical destruction by forming an S-nitrosothiol compound, was also evaluated. NAC potentiated the depressor response to unclipping (from 180 ± 5 mm Hg to 97 ± 3 mm Hg), and GFR and RPF increased by 80% and 35%, respectively. These effects of NAC appear to be NO dependent, as they were blocked by simultaneous administration of NAME. However, no significant differences were observed among groups in cumulative excretion of sodium and water, demonstrating that the hemodynamic effects of NAME and NAC after unclipping are due to mechanisms other than renal excretory changes. The results of the present study indicate that the cardiovascular depressor effects of unclipping are modulated by endothelium-derived nitric oxide.