Eur J Pharmacol [journal]
- Anti-angiogenicactivity of a new andrographolide derivative in zebrafish and HUVECs. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 26.
Andrographolide is among the most promising anti-tumor and anti-angiogenic components in Andrographis paniculata but its poor bioavailability and limited efficacy pose difficulties for its therapeutic development. Therefore, improving its pharmaceutical features and potency, by modifying its chemical structure, is desirable. In the present study, a new andrographolide derivative (AGP-40) was synthesized and characterized for its anti-angiogenic properties. Human umbilical vein endothelial cells (HUVECs) and zebrafish models were used to identify the anti-angiogenic activity of AGP-40. AGP-40 significantly suppressed the formation of blood vessels in zebrafish and inhibited proliferation, migration and tube formation in vitro. The anti-angiogenic effects of AGP-40 are at least partially mediated via the PI3K/Akt and MEK/Erk(1/2) signaling pathways. Furthermore, AGP-40 exhibited stronger anti-proliferative effects than andrographolide against A549, HepG2, Hela cancer cell lines. This study is the first to demonstrate the promising anti-angiogenic activity of the new andrographolide derivative AGP-40. Our results indicate that AGP-40 could serve as a potential therapeutic agent for the treatment and prevention of diseases associated with excessive angiogenesis.
- Effects of thienorphine on the contraction of isolated ureter and bladder of guinea pigs. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 18.
Opioid analgesics are widely used in moderate to severe pain including renal colic. Morphine is believed to cause spasm of ureter and affect the bladder contractions. Thienorphine is a partial opioid agonist that is a good candidate for the treatment of opioid dependence and pain. This study examined the effects of thienorphine on the guinea pig isolated ureter and bladder. The contractile amplitude of isolated ureter induced by KCl (40mM) was not influenced by thienorphine or buprenorphine, whereas morphine increased the amplitude of the isolated ureter. Thienorphine, buprenorphine or naloxone concentration-dependently antagonized the isolated ureter contraction induced by morphine. Thienorphine (1.0 - 32.0μM) or buprenorphine (1.0 - 32.0μM) had no effects on the spontaneous or acetylcholine (Ach) induced contractions of isolated bladder, but decreased the amplitude of the contractions of isolated bladder at 100μM concentration. Morphine (0.1 - 3.2mM) concentration dependently increased the spontaneous movement and Ach (1μM) induced contractions of isolated bladder. The mRNA levels of μ receptor in the ureter and bladder was as the same as that in the frontal cortex. In comparison, the mRNA levels of κ receptor, δ receptor and N/OFQ receptor was fewer than that in the frontal cortex. In summary, thienorphine has little influence on the guinea pig isolated ureter and bladder compared with morphine, which may result in a lack of adverse renal colic effects.
- In vivo neurochemical evidence that delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, inhibit acetylcholine efflux in the nucleus accumbens of freely moving rats. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 18.
Cholinergic neurons in the nucleus accumbens express delta- and mu-opioid receptors that are thought to inhibit neural activity. Delta- and mu-opioid receptors are divided into delta1- and delta2-opioid receptors and mu1- and mu2-opioid receptors, respectively. We analysed the roles of delta- and mu-opioid receptor subtypes in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. Other than naloxonazine, given intraperitoneally, delta- and mu-opioid receptor ligands were administered intracerebrally through the dialysis probe. Doses of these compounds indicate total amount (mol) over an infusion time of 30-60min. To monitor basal acetylcholine, a low concentration of physostigmine (50nM) was added to the perfusate. The delta1-opioid receptor agonist DPDPE (3 and 300 pmol) and delta2-opioid receptor agonist deltorphin II (3 and 30 pmol) decreased accumbal acetylcholine in a dose-related manner. DPDPE (300 pmol)- and deltorphin II (3 pmol)-induced reductions in acetylcholine were each inhibited by the delta1-opioid receptor antagonist BNTX (0.3 pmol) and delta2-opioid receptor antagonist naltriben (15 pmol), respectively. The mu-opioid receptor agonists endomorphin-1 and endomorphin-2 (6 and 30 nmol) decreased acetylcholine in a dose-related manner. Endomorphin-1- and endomorphin-2 (30 nmol)-induced reductions in acetylcholine were prevented by the mu-opioid receptor antagonist CTOP (3 nmol). The mu1-opioid receptor antagonist naloxonazine (15mg/kg ip), which inhibits endomorphin-1 (15 nmol)-induced accumbal dopamine efflux, did not alter endomorphin-1- or endomorphin-2 (30 nmol)-induced reductions in acetylcholine efflux. This study provides in vivo evidence for delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, that inhibit accumbal cholinergic neural activity.
- Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 23.
Depression is a serious mental disorder that is becoming more common. To better treat patients suffering from this illness, elucidation of the underlying psychopathological and neurobiological mechanisms of depression is needed. Based on the evidence, we sought to investigate the effects of hesperidin in a model of depression induced by olfactory bulbectomy (OB). C57BL/6 mice were treated with hesperidin (50mg/kg) and imipramine (10mg/kg, positive control) after OB induction. The brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin 1β (IL-1β) and interleukin 6 (IL-6) levels and acetylcholinesterase activity were analyzed in the hippocampus of the mice. The behavioral parameters were also verified in the model of depression induced by OB. This study demonstrated that OB increased the pro-inflammatory cytokines levels and acetylcholinesterase activity in the hippocampus, exploratory activity in the open field test and immobility in the forced swimming test in mice. In addition, OB decreased the BDNF and NGF levels in the hippocampus, grooming time in the splash test and memory consolidation in the Morris water maze task. Treatment with hesperidin, similar to imipramine, was effective in preventing these behavioral and neurochemical alterations. We suggest that the main targets of hesperidin are pro-inflammatory cytokine modulation, helping to maintain brain plasticity and acetylcholinesterase activity regulation, which are closely linked with antidepressant-like action, as shown by behavior tests. This study demonstrated that there is a pharmacological effect of hesperidin in alterations induced by OB in mice, indicating that hesperidin could be useful as a treatment for depression.
- Gene based therapies for kidney regeneration. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 22.
In this review we provide an overview of the expanding molecular toolbox that is available for gene based therapies and how these therapies can be used for a large variety of kidney diseases. Gene based therapies range from restoring gene function in genetic kidney diseases to steering complex molecular pathways in chronic kidney disorders, and can provide a treatment or cure for diseases that otherwise may not be targeted. This approach involves the delivery of recombinant DNA sequences harboring therapeutic genes to improve cell function and thereby promote kidney regeneration. Depending on the therapy, the recombinant DNA will express a gene that directly plays a role in the function of the cell (gene addition), that can regulate the expression of an endogenous gene (gene regulation), or even change the DNA sequence of endogenous genes (gene editing). Some interventions involve permanent changes in the genome whereas others are only temporary and leave no trace. Efficient and safe delivery are important steps for all gene based therapies and also depend on the mode of action of the therapeutic gene. Here we provide examples on how the different methods can be used to treat various diseases, which technologies are now emerging (such as gene repair through CRISPR/Cas9) and what the opportunities, perspectives, potential and the limitations of these therapies are for the treatment of kidney diseases.
- Extracellular matrix scaffolds as a platform for kidney regeneration. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 22.
Chronic and end stage renal disease (ESRD) have reached pandemic levels and pose a substantial public health burden. Unfortunately, available therapies lack efficacy in preventing progression to its end stage phase. Regenerative medicine promises to restore function of diseased organs among which the kidney, through two possible approaches: firstly, the maximization of the innate ability of tissues to repair or regenerate following injury; secondly, the ex vivo bio-fabrication of the organ in question. When regenerative medicine is applied to the setting of chronic or ESRD, it is intuitive that endeavors to improve renal repair, promote nephrogenesis in damaged kidneys, or the de novo engineering of transplantable kidneys, could have a major impact on the current management of this pandemic. Among the different regenerative medicine technologies currently under development, cell-on-scaffold seeding technology (CSST) - involving cells seeded throughout supporting scaffold structures made from biomaterials - is the most favorable candidate in the context of realistic clinical application. In this review, we outline and describe current investigations taking place in the field of CSST as it pertains to the restoration of kidney function.
- Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 22.
The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30μM) hyperpolarized the membrane and abolished action potential firing. NS309 (10μM) and SKA31 (100μM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10μM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10μM), a Kv7 channel blocker. BRL37344 (10μM), a β3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization.
- Amelioratingeffects of 1,8-Cineoleon LPS-induced human umbilical vein endothelial cell injury by suppressing NF-κB signaling in vitro. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 22.
1,8-Cineole (also known as eucalyptol) is a monoterpene that occurs naturally in many aromatic plants, 1,8-cineole has been reported to ameliorate dysfunction of endothelial cells. However, the mechanism of action of 1,8-cineole is incompletely understood. We investigated the protective effect of 1,8-cineole on lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) injury and the underlying mechanisms. HUVECs were preincubated with 1,8-cineole for 1.5h, then exposed to LPS for 12h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase leakage assays showed 1,8-cineole reduced LPS-induced HUVEC injury significantly. Results from enzyme linked immunosorbent assays revealed that 1,8-cineole suppressed LPS-induced secretion of interleukin-6 and interleukin-8, and recovered nitric oxide to normal levels. 1,8-Cineole decreased phosphorylation of nuclear factor-kappa B (NF-κB) p65 and expression of inducible nitric oxide synthase, and simultaneously improved protein levels of endothelial nitric oxide synthase. Immunofluorescence confirmed 1,8-cineole moderates nuclear translocation of NF-κB. These results suggest that 1,8-cineole ameliorates HUVEC dysfunction significantly, and that this effect at least involves NF-κB suppression.
- Crocetin protects ultraviolet A-induced oxidative stress and cell death in skin in vitro and in vivo. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 21.
Crocetin, the aglycone of crocin, is a carotenoid found in fruits of gardenia (Gardeina jasminoides Ellis) and saffron (Crocus sativus L.). We investigated the protective effects of crocetin against ultraviolet-A (UV-A)-induced skin damage and explored the underlying mechanism. Human skin-derived fibroblasts cells (NB1-RGB) were damaged by exposure to UV-A irradiation (10J/cm(2)). Crocetin protected these cells against cell death and reduced the production of reactive oxygen species induced by UV-A irradiation. Crocetin treatment also suppressed induction of caspase-3 activation by UV-A irradiation. The effects of crocetin against oxidative stress were also examined by imaging of Keap1-dependent oxidative stress detector (OKD) mice. UV-A irradiation upregulated oxidative stress in the OKD mice skin, while crocetin administration (100mg/kg, p.o.) ameliorated this oxidative stress. Crocetin administration also decreased lipid peroxidation in the skin. These findings suggest that crocetin its observed protective effects against UV-A induced skin damage by reducing reactive oxygen species production and cell apoptosis.
- Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. [JOURNAL ARTICLE]
- Eur J Pharmacol 2016 Jul 20.
Medical ozone reduced inflammation, IL-1β, TNF-α mRNA levels and oxidative stress in PG/PS-induced arthritis in rats. The aim of this study was to investigate the medical ozone effects in patients with rheumatoid arthritis treated with methotrexate and methotrexate+ozone, and to compare between them. A randomized clinical study with 60 patients was performed, who were divided into two groups: one (n = 30) treated with methotrexate (MTX), folic acid and Ibuprophen (MTX group) and the second group (n = 30) received the same as the MTX group + medical ozone by rectal insufflation of the gas (MTX+ozone group). The clinical response of the patients was evaluated by comparing Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), Anti-Cyclic Citrullinated (Anti-CCP) levels, reactants of acute phase and biochemical markers of oxidative stress before and after 20 days of treatment. MTX+ozone reduced the activity of the disease while MTX merely showed a tendency to decrease the variables. Reactants of acute phase displayed a similar picture. MTX+ozone reduced Anti-CCP levels as well as increased antioxidant system, and decreased oxidative damage whereas MTX did not change. Glutathione correlated with all clinical variables just after MTX+Ozone. MTX + Ozone increased the MTX clinical response in patients with rheumatoid arthritis. No side effects were observed. These results suggest that ozone can increase the efficacy of MTX probably because both share common therapeutic targets. Medical ozone treatment is capable of being a complementary therapy in the treatment of rheumatoid arthritis.