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The wingless/integrase‐1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic‐acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA‐Al(OH)3 administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK‐974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5‐HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5‐HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5‐HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK‐3β and WNT5A levels, which had been induced by airway inflammation, in a dose‐dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad‐2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin‐17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK‐3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model. [ABSTRACT FROM AUTHOR]

As standard therapy for prostate cancer, radical prostatectomy causes cavernous nerve (CN) injury and increases fibrosis and hypoxia-induced penile structural alterations. This study aimed to determine the potential beneficial effects of adipose-derived stem cells (ADSCs) and l-arginine alone or in combination on the penile erection in a rat model of erectile dysfunction caused by bilateral cavernous nerve transection (CNT). Male rats (n = 35) were randomized into five groups: Sham-operated; CNT (4-weeks); CNT plus ADSCs (1 × 106 cells by intracavernosal injection); CNT plus l-arginine (4 weeks, 10 mg/kg/day, oral); and ADSCs combined with l-arginine in CNT. In vivo erectile responses and in vitro relaxant responses were measured. Western blot and immunohistochemistry analyses were used to determine the expression and localization of endothelial nitric oxide synthase, neuronal nitric oxide synthase, transforming growth factor-beta 1, hypoxia-inducible factor-1 alpha (HIF-1α), and apoptosis markers (Bax and Bcl-2). The ratio of smooth muscle to collagen and nerve regeneration were calculated using Masson's trichrome and nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining. The combined treatment restored diminished erectile responses, endothelium-dependent acetylcholine, and electrical field stimulation-induced relaxation of the corpus cavernosum in rats with CNT, whereas either monotherapy produced only partial improvements. All treatment regimens restored increases in the protein expression of HIF-1 and Bax in rats with CNT. The decrease in smooth muscle mass and NADPH-diaphorase-positive nerve fibers was partially ameliorated by monotherapy, whereas combined therapy led to recovery. These findings indicate that combined treatment with ADSCs and l-arginine may restore erectile function in rats with CNT by inhibiting hypoxia-induced neurotoxicity and preserving endothelium function and smooth muscle content. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify the effect of trimetazidine (TMZ), an antianginal drug, on detrusor smooth muscle (DSM) contractility and its possible mechanisms of action. Methods: We performed in-vitro contractility studies on isolated mouse DSM strips and investigated the effect of TMZ on Ca2+ levels in fura-2-loaded A7r5 cells. Key findings: TMZ (300 or 1000 µM) inhibited carbachol (CCh)- and KCl-induced contractions and produced a concentration-dependent (10–1000 µM) relaxation in KCl-precontracted DSM strips. TMZ-induced relaxation was markedly decreased by BaCl2, an inward-rectifying K+ channel blocker, but was not altered by preincubation with tetraethylammonium, glibenclamide, 4-aminopyridine, propranolol, L-NAME or methylene blue. TMZ (300 or 1000 µM) reduced both the CaCl2-induced contraction of depolarized DSM strips under Ca2+-free conditions and the CCh-induced contraction of DSM strips preincubated with nifedipine in Ca2+-containing Krebs solution. Furthermore, TMZ (1000 µM) significantly decreased the Ca2+ levels in fura-2-loaded A7r5 cells. Conclusions: TMZ decreased DSM contractility and caused a concentration-dependent relaxation of the tissue possibly through its actions on Ca2+ transients and K+ channels. Our results provide preclinical evidence that TMZ would be a potential candidate to treat disorders related to the overactivity of the bladder. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used in a wide variety of diseases due to their analgesic and anti‐inflammatory effects, but their usage have been limited due to significant ulcerogenic side effects. In the present study, we aimed to evaluate the effect of α‐lipoic acid (ALA) treatment on the anti‐inflammatory activity of indomethacin (Indo) as well as the possible therapeutic effect of ALA on high dose Indo‐induced gastropathy in female mice. Mice were treated with Indo (5 or 30 mg/kg, p.o) alone or in combination with ALA (50, 100 or 200 mg/kg, i.p). in vivo anti‐inflammatory effect was evaluated by formalin‐induced paw edema measured as paw thickness and edema. Gastric damage was evaluated macroscopically and histologically by scoring mucosal hemorrhage, erosion, edema and inflammation. To our results, Indo was ineffective at 5 mg/kg, but co‐treatment with Indo and ALA significantly reduced paw edema, implying that ALA augmented the anti‐inflammatory effect of subtherapeutic dose of Indo. However, ALA was not able to induce a further increase in the anti‐inflammatory effect of Indo at 30 mg/kg. Unlike the treatment with Indo at 5 mg/kg, Indo at 30 mg/kg caused severe gastric damage that prevented by co‐treatment with ALA. These results suggest that combination of ALA with NSAIDs can both increase anti‐inflammatory effect and prevent NSAIDs‐induced gastric damage. ALA would be promising adjuvant that can reduce dose for effective NSAID therapy, which improves safety profile of NSAIDs especially in cases long‐term administration of high dose needed. [ABSTRACT FROM AUTHOR]

Novel aryl/alkyl azole derivative compounds C1 and C2 were screened for in vivo anti-nociceptive and anti-inflammatory activities by using the hot plate test and formalin-induced hind paw edema test, respectively. The ability of these compounds to inhibit cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenase (5/15-LOX) were evaluated in vitro by using a colorimetric method. C1 (30 and 50 mg/kg, i.p.) and C2 (3 and 30 mg/kg, i.p.) increased the latency to withdrawal in the hot plate test, indicating an anti-nociceptive activity. C1(30 and 50 mg/kg) and C2 (3,30 and 50 mg) were able to decrease formalin-induced edema, indicating their anti-inflammatory properties. C1and C2 exhibited inhibitory effects on the activity of COX(1-2) and 15-LOX. However, neither C1 nor C2 showed an inhibitory effect on 5-LOX. This study demonstrates that C1 and C2 have anti-nociceptive and anti-inflammatory activities, that are partially mediated by inhibition of COX and LOX enzymes. Our results suggest that C1and C2, novel aryl/alkyl azole compounds, could serve as lead compounds to develop novel therapeutic options for the treatment of pain and inflammation. [ABSTRACT FROM AUTHOR]

Author(s): Sena F. Sezen [1]; Ahmet Hoke [2]; Arthur L. Burnett [1]; Solomon H. Snyder [3] To the editor Erectile dysfunction following radical prostatectomy is common even with presumably intact [...]

We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterize erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6) and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS-/-) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. I Sickle mice, C6' also attenuated the increased ROS markers gp91phox, 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic-/- erection response of dNOS-/- mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy. [ABSTRACT FROM AUTHOR]

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Background Diabetes mellitus-induced erectile dysfunction (DMED) is a common urological complication of diabetes, and current drugs often fail to provide an effective treatment. Smad2/3 signaling-mediated corporal fibrosis has a critical role in the molecular basis of DMED. Aim We investigated the effect of Niclosamide (Nic), an antihelmintic drug with antifibrotic effects, on erectile function in a rat DMED model. Methods Male Sprague Dawley rats were injected intraperitoneally (i.p) with streptozotocin (75 mg/kg) to induce diabetes. At week 8, both diabetic and nondiabetic rats were treated with Nic (10 mg·kg−1/day; i.p) or vehicle for 4 weeks. At week 12, erectile function was evaluated as intracavernous pressure (ICP) response to the electrical stimulation of the cavernous nerve (CN). Penile tissues were harvested for Masson's trichrome staining or western blotting to determine corporal fibrosis and Smad2/3 pathway-related protein expression, respectively. Outcomes At the end of the experimental protocol, in vivo erectile function was assessed by measuring the ratio of ICP/ mean arterial pressure (MAP) and total ICP following CN stimulation. Smooth muscle content and collagen fibers were evaluated by Masson's trichrome staining of the penile tissues. The expressions of fibrosis-related proteins (Smad2, Smad3, fibronectin) were determined using western blotting in the penile tissues. Results Erectile function, as determined by the maximum ICP/MAP and total ICP/MAP ratios, was drastically decreased in diabetic rats. Corporal tissues of diabetic rats were severely fibrotic with a significant increase in collagen fibers and a marked reduction in smooth muscle content. Also, the protein expressions of phosphorylated (p-)Smad2, p-Smad3 and fibronectin were significantly increased in the penis of diabetic rats. Both functional and molecular alterations in DMED were effectively reversed by Nic-treated diabetic rats without a glycemic alteration. Clinical Implications Nic could be a promising candidate for the treatment of DMED due to its antifibrotic effects. Strengths and Limitations The present study provides the first evidence that Nic has beneficial effect on erectile dysfunction by attenuating corporal fibrosis in a rat model of DMED. The effect of Nic on penile endothelial function and the other potential underlying mechanisms needs to be further elucidated. Conclusions Nic improved erectile function in DMED rats possibly suppressing penile fibrosis by inhibiting Smad2/3 signaling. These results suggest a potential therapeutic repurposing of Nic as an adjuvant treatment in DMED. [ABSTRACT FROM AUTHOR]