[Rose-scented geranium essential oil from Algeria (Pelargonium graveolens L'Hérit.): Assessment of antioxidant, anti-inflammatory and anticancer properties against different metastatic cancer cell lines]. / Essence aromatique du Géranium Odorant (Pelargonium graveolens L'Hérit.) d'Algérie : exploration des propriétés antioxydante, anti-inflammatoire et anticancéreuse (anti-angiogénique et cytotoxique), in vitro et in ovo, vis-à-vis de différentes lignées cellulaires cancéreuses métastasiques.

INTRODUCTION: The study of natural products is one of the strategies implemented for the discovery of new compounds that can be used in cancer therapy. Aromatic herbs and medicinal plants found in Algeria and their anti-angiogenesis and cytotoxic potentials against cancer have not been much explored. OBJECTIVES: Our work aimed to evaluate the antioxidant, anti-inflammatory and anticancer properties of the essential oil (EO) extracted from rose-scented geranium (Pelargonium graveolens) and its major (citronellol) and characteristic (linalool) constituents. RESULTS: The chemical composition of EO was determined with chromatographic analysis and revealed the presence of citronellol as the major compound (25.84%). A strong chelating power of terpene alcohols (IC50=1.58±0.23mg/mL for citronellol) was found, with a significant difference (P<0.05) compared with the standard antioxidants used (L-ascorbic acid and butylated hydroxyanisole). The EO is distinguished by an interesting anti-inflammatory effect with the lowest IC50 (4.63±0.3mg/mL), and it constitutes a good stabilizer of the erythrocyte membrane. Citronellol also exhibited the best anti-inflammatory effect (IC50=0.74±0.09mg/mL). We also assessed the anticancer effect of EO on two main pathways involved in cancer development, angiogenesis and cell proliferation, using in ovo bioassays with a chorio-allantoic membrane (CAM) of chicken eggs and in vitro assays of its cytotoxicity on different metastatic breast cancer (MDA-MB-231), gastric (AGS) and melanoma (MV3) cell lines. In the CAM model, the density of micro-vessels is 75±10 in the group supplemented with EO compared to 140±9 for the control group (b-FGF). In addition, the EO significantly reduced the number of newly formed vessels. The cytotoxicity was evaluated using the cell proliferation inhibition method and cell viability was measured using the MTT test. Results revealed that the treatment of cancer lines with different concentrations of EO reduces the rate of cell viability in a dose-dependent manner. EO showed the greatest cytotoxicity on the AGS line with an inhibition rate of 92.87±0.13% at the highest dose (4µL/mL), followed by the MV3 line (88.76±0.96%). CONCLUSION AND PROSPECTS: Data demonstrated that rose-scented geranium EO has an antitumor potential on metastatic cancer cell lines. It is distinguished by its antiproliferative, anti-angiogenic, and anti-inflammatory activities. Medicinal plants might contain new molecules, with new structures, which could become lead candidate among future anticancer drugs.

Lycopene nanoparticles promotes osteoblastogenesis and inhibits adipogenesis of rat bone marrow mesenchymal stem cells.

OBJECTIVE: Lycopene is a carotenoid and antioxidant with potent singlet oxygen quenching ability that reduces oxidative stress and promotes bone health. However, the cellular mechanisms by which lycopene influences bone metabolism are not known. MATERIALS AND METHODS: The present study investigated the effects of lycopene nanoparticles on the differentiation of rat bone marrow-derived mesenchymal stem cells into osteoblasts or adipocytes. RESULTS: In osteogenic medium, lycopene supplementation dose-dependently enhanced osteoblast differentiation, as evidenced by the transcription of Alpl, Runx2, Col1a1, Sp7, and Bglap, higher alkaline phosphatase activity, osteocalcin secretion and extracellular matrix mineralisation seen with Alizarin red S staining, and increased haem oxygenase levels. By contrast, lycopene in adipogenic medium inhibited adipocyte differentiation evidenced by decreases in the transcription of Tnfsf11, Tnfrsf11b, Pparg, Lpl, and Fabp4 and reduced fat accumulation observed by Oil Red O staining. CONCLUSIONS: Lycopene nanoparticles may promote bone health and are considered as a potential candidate for the prevention and/or treatment of bone loss conditions.

[Background and current use of adjuvants for regional anesthesia : From research to evidence-based patient treatment]. / Hintergrund und aktueller Einsatz von Adjuvanzien für die Regionalanästhesie : Aus der Forschung in die evidenzbasierte Patientenversorgung.

The discovery of the local anaesthetic effect by blocking sodium ion channels was a milestone in anaesthesia but was soon limited by sometimes life-threatening toxic effects of the local anaesthetics. By developing novel local anaesthetics and also by adding so-called adjuvants, attempts have been made to limit these life-threatening events. This article focuses on the historic background and the current state of the use of these adjuvants for regional anaesthesia. Adding epinephrine, clonidine or dexmedetomidine, but only as a single dose, results in a faster onset, longer duration of action and increased intensity of neuronal blockade of regional anaesthesia. The benefits of adding sodium bicarbonate, on the other hand, are relatively minor and, therefore, clinically negligible. Although increasing evidence in the literature suggests an improvement and prolongation of the analgesic effect after axonal administration of opioids, which can also be given continuously, systemic effects are not fully ruled out due to the increased incidence of central side effects. The partial local anaesthetic effects of opioids cannot always be distinguished from opioid receptor-specific effects. Mechanistic studies postulate a functional coupling of opioid receptors in injured rather than in intact peripheral nerves. Recent studies have identified glucocorticoid and mineralocorticoid receptors predominantly on peripheral nociceptive nerve fibers. This is consistent with numerous clinical reports of a marked prolongation of the local anaesthetic effect. In addition to the known genomic effects of steroids that occur via a change in gene expression of pain-sustaining protein structures, faster non-genomic effects are also discussed, which occur via a change in intracellular signaling pathways. In summary, new insights into mechanisms and novel results from clinical trials will help the anaesthesiologist in the decision to use adjuvants for regional anaesthesia which, however, requires to weigh the individual patient's benefits against the risks.

Greasing the wheels of managing overweight and obesity with omega-3 fatty acids.

The epidemic of overweight and obesity around the world and in the US is a major public health challenge, with 1.5 billion overweight and obese adults worldwide, and 68% of US adults and 31% of US children and adolescents overweight or obese. Obesity leads to serious health consequences, including an increased risk of type 2 diabetes mellitus and heart disease. Current preventive and medical treatments include lifestyle modification, medication, and bariatric surgery in extreme cases; however, they are either not very efficacious or are very expensive. Obesity is a complex condition involving the dysregulation of several organ systems and molecular pathways, including adipose tissue, the pancreas, the gastrointestinal tract, and the CNS. The role of the CNS in obesity is receiving more attention as obesity rates rise and treatments continue to fail. While the role of the hypothalamus in regulation of appetite and food intake has long been recognized, the roles of the CNS reward systems are beginning to be examined as the role of environmental influences on energy balance are explored. Omega-3 polyunsaturated fatty acids are essential nutrients that play a beneficial role in several disease processes due to their anti-inflammatory effects, modulation of lipids, and effects on the CNS. Omega-3 fatty acids, specifically EPA and DHA, have shown promising preliminary results in animal and human studies in the prevention and treatment of obesity. Given their effects on many of the pathways involved in obesity, and specifically in the endocannabinoid and mesocorticolimbic pathways, we hypothesize that EPA and DHA supplementation in populations can reduce the reward associated with food, thereby reduce appetite and food intake, and ultimately contribute to the prevention or reduction of obesity. If these fatty acids do harbor such potential, their supplementation in many parts of the world may hold great promise in reducing the global burden of obesity.

Protective effects of Morus alba leaves extract on ocular functions of pups from diabetic and hypercholesterolemic mother rats.

Phytotherapy is frequently considered to be less toxic and free from side effects than synthetic drugs. Hence, the present study was designed to investigate the protective use of crude water extract of Morus alba leaves on ocular functions including cataractogenesis, biochemical diabetic and hypercholesterolemic markers, retinal neurotransmitters and retinopathy of rat pups maternally subjected to either diabetes and/or hypercholesterolemia. Application of crude water extract of Morus alba resulted in amelioration of the alterations of maternal serum glucose, LDL, HDL, total cholesterol and creatine phosphokinase activity as well as retinal neurotransmitters including acetylcholine (ACE), adrenaline (AD), nor-adrenaline (NAD), serotonin (5-HT), histamine (HS), dopamine (DA) and gamma amino butyric acid (GABA). The retina of pups of either diabetic and/or hypercholesterolemia mothers exhibited massive alterations of retinal neurotransmitters. The alterations of retinal neurotransmitters were correlated with the observed pathological alterations of retinal pigmented epithelium, photoreceptor inner segment and ganglion cells and increased incidence of DNA fragmentation and apoptosis cell death. However, protection with Morus alba extract led to amelioration of the pathological alterations of retinal neurons and estimated neurotransmitters. Furthermore, a striking incidence of cataract was detected in pups of either diabetic and/or hypercholesterolemic mothers. Highest cataractogenesis was observed in pups of combined -treated groups. Our data indicate that experimental maternal diabetes alone or in combination with hypercholesterolemia led to alteration in the ocular structures of their pups, with an increasing incidence of cataract and retinopathy, and the effects of the extract might be attributed to the hypoglycaemic, antihypercholesterolemic and anti-oxidative potential of flavonoids, the major components of the plant extract.

Comparative antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist (XV454) and abciximab (c7E3) in flow models of thrombosis.

Glycoprotein (GP) IIb/IIIa is pivotal in homotypic platelet aggregation and may also be involved in the heterotypic adhesion of leukocytes and tumor cells to platelets. This study was primarily undertaken to compare the antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist, XV454, to that of abciximab in 2 flow models of platelet thrombus formation: (1) direct shear-induced platelet aggregation imposed by a cone-and-plate rheometer and (2) platelet adhesion onto von Willebrand factor (vWF)/collagen I followed by aggregation in a perfusion system. XV454 inhibited platelet aggregation in a concentration-dependent manner in both experimental models. Maximal inhibition of aggregation was achieved by XV454 at approximately 70% receptor occupancy, which is lower than the >/=85% previously reported for abciximab. At similar levels of receptor blockade (approximately 45%), XV454 appeared to be relatively more effective than abciximab in suppressing platelet aggregation. Neither XV454 nor abciximab inhibited platelet adhesion to collagen. Pretreatment of surface-adherent platelets with either XV454 or abciximab inhibited the attachment of monocytic THP-1 cells under flow. In contrast, the rapidly reversible GPIIb/IIIa inhibitor orbofiban failed to suppress these heterotypic interactions. These findings demonstrate that XV454 is a potent GPIIb/IIIa antagonist with a long receptor-bound lifetime like abciximab and may be beneficial for the treatment/prevention of thrombotic complications.

Platelet glycoprotein IIb/IIIa receptor antagonists derived from isoxazolidines.

A series of isoxazolidines has been synthesized as mimetics of the RGD sequence and was evaluated as antagonists of the platelet glycoprotein IIb/IIIa receptor. These compounds were shown to be highly potent GPIIb/IIIa antagonists, exhibiting submicromolar potencies.

Oral antiplatelet efficacy of the platelet GPIIb/IIIa antagonist, DMP754 in non-human primates.

Binding kinetic studies with XV459, the active form of DMP754, demonstrated comparable binding kinetics (Kd and Koff) with platelets obtained from either human or baboons which were different from that with platelets obtained from dogs. Therefore, the present study was undertaken to evaluate the antiplatelet efficacy of DMP754 following oral administration in baboons. The dose levels evaluated were 0.1 and 1.0 mg/kg, IV and 0.1, 0.3, 1.0, and 3.0 mg/kg, oral of DMP754. Oral doses of DMP754 resulted in dose- and time-related inhibition of platelet aggregation along with a modest effect on bleeding time prolongation. DMP754 at similar oral doses had 24 hours of antiplatelet effects in baboon as compared to 8-12 hours duration of antiplatelet efficacy in dogs. At maximal antiplatelet doses DMP754 demonstrated no significant effects on platelet count, clinical chemistry or hemodynamic profiles in baboons. These data suggest that DMP754 is a potent orally active antiplatelet agent with extended duration after once a day oral administration in non-human primate.

Corticotropin-releasing factor in antinociception and inflammation.

Corticotropin-releasing factor (CRF) plays a major role at the level of the hypothalamus and pituitary to control the body's response mechanisms to stressful stimuli. The recent discovery of CRF outside the central nervous system suggests that CRF may well play a similar role in peripheral tissues, most likely in a paracrine manner. While its effects in many other peripheral tissues is not known yet, CRF and its receptors are upregulated in inflammatory pain states pointing to a key role under these circumstances. Indeed, locally expressed CRF seems to act on CRF receptors on immune cells which have migrated into the area of the inflamed tissue, and induce the release of opioid peptides synthesized within these immune cells. These opioids subsequently act on peripheral opioid receptors located on peripheral sensory nerves to inhibit the transmission of painful stimuli. CRF may also affect the inflammatory response; however, these data are still controversial. The peripheral paracrine effects of CRF may be similar to those of hypothalamic CRF, i.e., to counterbalance local stressful events, such as inflammation and pain, so that they do not threaten the homeostasis of the body. Interestingly, CRF-like peptides have been identified not only in mammalians, but also in species such as the frog (Stenzel-Poore et al., 1992, Mol. Endocrinol. 6, 1716) and the teleost fish (Okawara et al., 1988, Proc. Natl. Acad. Sci. USA 85, 8439) indicating that this is a peptide that has been conserved over a long period (200 million years) across species (Lederis et al., 1990, Prog. Clin. Biol. Res. 342, 467) and that the release of ACTH-like peptides by peptides of the CRF family may represent an ancestral type of stress response (Ottaviani et al., 1992, Gen. Comp. Endocrinol. 87, 354; Tran et al., 1990, Gen. Comp. Endocrinol. 78, 351).