PCSK 9: A Link Between Inflammation and Atherosclerosis.

Proprotein convertase subtilisin/Kexin 9 (PCSK 9) is revealed to be a key player in lipid metabolism and, therefore, in the development and progression of atherosclerosis. PCSK 9 binds to the low-density lipoprotein (LDL) receptor, induces its degradation, and increases circulating blood LDL. As a result, PCSK 9 inhibitors represent an essential pillar in cardiovascular risk reduction therapies due to their highly sufficient LDL decreasing properties. While the influence of PCSK 9 on lipid metabolism has been widely investigated, the full pathophysiological spectrum of PCSK 9 is yet to be determined. Statins have already been demonstrated to have beneficial anti-inflammatory effects. In this context, evidence suggests that PCSK 9 also interferes with inflammatory processes, thereby contributing to the development of atherosclerosis. As lipid metabolism on its own affects inflammatory processes, it is difficult to distinguish between lipid-dependent and -independent inflammatory properties of PCSK 9. A body of evidence has revealed that PCSK9 LDL-independently regulates the secretion of pro-inflammatory cytokines and inflammation-underlying pathways in vascular walls, whereas recent observations suggest that PCSK9 also interacts with lectin-like oxidized LDL receptor-1 (LOX-1) and dampens inflammatory responses through LDL reduction. In conclusion, this review provides mounting evidence indicating how PCSK9 promotes vascular inflammation and subsequent atherosclerosis to shed light on the anti-inflammatory effects of PCSK9 inhibitors in the prevention of atherosclerosis.

Discordance between eNOS phosphorylation and activation revealed by multispectral imaging and chemogenetic methods.

Nitric oxide (NO) synthesized by the endothelial isoform of nitric oxide synthase (eNOS) is a critical determinant of vascular homeostasis. However, the real-time detection of intracellular NO-a free radical gas-has been difficult, and surrogate markers for eNOS activation are widely utilized. eNOS phosphorylation can be easily measured in cells by probing immunoblots with phosphospecific antibodies. Here, we pursued multispectral imaging approaches using biosensors to visualize intracellular NO and Ca2+ and exploited chemogenetic approaches to define the relationships between NO synthesis and eNOS phosphorylation in cultured endothelial cells. We found that the G protein-coupled receptor agonists adenosine triphosphate (ATP) and histamine promoted rapid increases in eNOS phosphorylation, as did the receptor tyrosine kinase agonists insulin and Vascular Endothelial Growth Factor (VEGF). Histamine and ATP also promoted robust NO formation and increased intracellular Ca2+ By contrast, neither insulin nor VEGF caused any increase whatsoever in intracellular NO or Ca2+-despite eliciting strong eNOS phosphorylation responses. Our findings demonstrate an unexpected and striking discordance between receptor-modulated eNOS phosphorylation and NO formation in endothelial cells. Previous reports in which phosphorylation of eNOS has been studied as a surrogate for enzyme activation may need to be reassessed.

Reversal of heart failure in a chemogenetic model of persistent cardiac redox stress.

We previously described a novel "chemogenetic" animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [18F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress.NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other "interventional" animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer.

The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment. To this purpose, a number of databases were used to search for the cytotoxic/anticancer effects of andrographolide in pre-clinical and clinical studies. Among 1703 identified literature articles, 139 were included in this review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre-clinical trials, respectively. Among the model systems, cultured cell lines appeared as the most frequently (79.14%) used, followed by in vivo models using rodents, among others. Furthermore, andrographolide was found to exert cytotoxic/anticancer effects on almost all types of cell lines with the underlying mechanisms involving oxidative stress, cell cycle arrest, anti-inflammatory and immune system mediated effects, apoptosis, necrosis, autophagy, inhibition of cell adhesion, proliferation, migration, invasion, anti-angiogenic activity, and other miscellaneous actions. After careful consideration of the relevant evidence, we suggest that andrographolide can be one of the potential agents in the treatment of cancer in the near future.

Rapamycin protects testes against germ cell apoptosis and oxidative stress induced by testicular ischemia-reperfusion.

OBJECTIVES: Rapamycin is an immunosuppressant compound with a broad spectrum of pharmaco-logical activities. In recent years, it has been used successfully to decrease ischemia-reperfusion injury in several organ systems. The purpose of the present study was to examine the effect of rapamycin on testicular ischemia-reperfusion injury. MATERIALS AND METHODS: Seventy-two adult male Wistar rats were divided into six groups: control (group1), sham-operated (Group2), T/D + DMSO as vehicle group (group3), and groups 4-6; respectively received 0.5, 1, and 1.5 mgkg-1 of rapamycin, IP 30 min before detorsion. Ischemia was achieved by twisting the right testis 720° clockwise for 1 hr. The right testis of 6 animals from each group were excised 4 hr after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and TUNEL test in right testis of 6 animals per group, 24 hr after detorsion. RESULTS: Testicular T/D caused increases in the apoptosis, malondialdehyde (MDA), and caspase-3 levels and decreases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in ipsilateral testis (P<0.001). The rats treated with rapamycin had significant decreases in the MDA and caspase-3 levels and significant increases in the SOD, CAT and GPx activities in ipsilateral testis compared with the T/D group (P<0.001); germ cell apoptosis was decreased, and MSTD was improved. CONCLUSION: Rapamycin administration during testicular torsion decreased ischemia/reperfusion (I/R) cellular damage.

An orbital hydatid cyst involving inferior rectus muscle: A case report.

The orbital hydatid cyst is a rare entity and although most of them are located in superolateral and superomedial angles of orbits, involvement of inferior sites is uncommon. We report a 12-year-old case of primary hydatid cyst situated in inferior rectus muscle which was undergone surgical removal. Magnetic resonance imaging (MRI) was used for differential diagnosis of hydatid cyst. Moreover, histological analysis was performed, after the cyst removal, to confirm the diagnosis. Early clinical and radiological evaluations and subsequent surgical excision is the mainstay of treatment and should be performed to prevent severe complications caused by the advanced and ruptured cysts.

Minocycline Attenuates Depressive-Like Behaviour Induced by Rat Model of Testicular Torsion: Involvement of Nitric Oxide Pathway.

Testicular torsion/detorsion (T/D) can induce depression in pre- and post-pubertal patients. This study was conducted to investigate the psychological impact of testicular torsion and mechanism underlying its depressive-like behaviour, as well as antidepressant-like activity of minocycline and possible involvement of nitric oxide (NO)/cyclic GMP pathway in this paradigm in male rats undergoing testicular T/D. Unilateral T/D was performed in 36 male adult Wistar rats, and different doses of minocycline were injected alone or combined with N(ω) -nitro-l-arginine methyl ester (l-NAME), non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), specific inducible NOS inhibitor; l-arginine, an NO precursor; and selective PDE5I, sildenafil. After assessment of locomotor activity in open-field test, immobility times were recorded in the forced swimming test (FST). Moreover, 30 days after testicular T/D, testicular venous testosterone and serum nitrite concentrations were measured. A correlation was observed between either a decrease in plasma testosterone or an increase in serum nitrite concentrations with prolongation in immobility time in the testicular T/D-operated rats FST. Minocycline (160 mg/kg) exerted the highest significant antidepressant-like effect in the operated rats in the FST (p < 0.001). Furthermore, combination of subeffective doses of minocycline (80 mg/kg) and either l-NAME (10 mg/kg) or AG (50 mg/kg) demonstrated a significant robust antidepressant-like activity in T/D group (p < 0.01). Consequently, NO/cGMP pathway was involved in testicular T/D-induced depressive-like behaviour and antidepressant-like activity of minocycline in the animal model. Moreover, a contribution was observed between either decreased testosterone or elevated serum nitrite levels and depressive-like behaviour following testicular T/D.

Hepatoprotective, antinociceptive and antioxidant activities of cimetidine, ranitidine and famotidine as histamine H2 receptor antagonists.

The antioxidant, antinociceptive and hepatoprotective effects of H(2) receptor blockers were examined with different experimental models. Antioxidant activities were determined by employing various in vitro assay systems such as 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical-scavenging activity assays, reducing power determination assays, nitric oxide-scavenging activity assays and hydrogen peroxide-scavenging activity assays. Antinociceptive effects were determined using the hot plate test in mice. The hepatoprotective effects of cimetidine, ranitidine and famotidine against hepatotoxicity induced by carbon tetrachloride (CCl(4) ) were determined by measuring the levels of serum enzymes alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities in mice. We found that the IC(50) values of cimetidine, ranitidine and famotidine on DPPH radical-scavenging activity were 671±28, 538±21 and 955±43 µg/mL, respectively. Famotidine showed very strong nitric oxide-scavenging activity. All three compounds showed very weak hydrogen peroxide-scavenging activity. Moreover, the compounds did not exhibit any reducing power activity until concentrations of 1.6 mg/mL. All compounds also showed a dose-dependent and marked analgesic activity in mice relative to controls. Pretreatment of mice with cimetidine, ranitidine or famotidine for three consecutive days reduced CCl(4)-induced hepatotoxicity in mice. Treatment with 200 mg/kg ranitidine reduced AST, AST and ALP serum levels, while 200 and 40 mg/kg of cimetidine and famotidine, respectively, reduced AST and ALP serum levels. H(2) blockers exhibited varying levels of antioxidant activities in various assays. Our results indicate that the antioxidant activities of H(2) blockers have an analgesic activity and protective effect on CCl(4)-induced hepatotoxicity in mice. These effects were greater with ranitidine than with the other compounds.

Heavy metals (Zn, Pb, Cd and Cr) in fish, water and sediments sampled form Southern Caspian Sea, Iran.

Environmental pollution is a worldwide problem, heavy metals belonging to the most important pollutants. The progress of industries has led to increased emission of pollutants into ecosystems. Southern Caspian Sea coast is one of the most important aquasystems at the eastern south of Caspian Sea, which receives effluents discharges from heavily industrialized and highly populated settlements. Metals tend to accumulate in water and move up through the food chain. So, studies to ascertain the level of heavy metals in environment and determine potentially hazardous levels for human are necessary. In this investigation, concentration of four heavy metals (zinc [Zn], chromium (Cr), cadmium, [Cd] and lead [Pb]) in three species of most-consumed fishes, water and sediments have been determined. Samples were collected from 10 stations along the Southern coast of Caspian Sea, in spring 2008. Heavy metal concentrations were measured by graphite furnace atomic absorption spectrometry. Then, the data were analyzed by means of one-way analysis of variance (ANOVA) statistical analysis. The results showed that the highest concentration of heavy metals in water and fish and sediment samples were related to Pb and Zn. The minimal and maximal concentrations of these metals in fishes, water and sediments were 53.67-2360.67 and 50.36-2497.25 for Pb and Zn, respectively. However, the observed heavy metals concentrations in fish, water and sediments were below the recommended limits. The investigation showed elevating levels of heavy metals in environment. Thus, a serious notification to industrial and manmade pollution, which can lead to ecosystem and food chain contamination, is necessary.