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Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility. AIM: To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck. METHODS: Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measuremen

Endoplasmic reticulum stress leads to lipid accumulation through upregulation of SREBP-1c in normal hepatic and hepatoma cells.

Endoplasmic reticulum stress (ERS) has been found in non-alcoholic fatty liver disease. The study was to further explore the mechanistic relationship between ERS and lipid accumulation. To induce ERS, the hepatoblastoma cell line HepG2 and the normal human L02 cell line were exposed to Tg for 48 h. RT-PCR and Western blot were performed to evaluate glucose-regulated protein (GRP-78) expression as a marker of ERS. ER ultrastructure was assessed by electron microscopy. Triglyceride content was examined by Oil Red O staining and quantitative intracellular triglyceride assay. The hepatic nuclear s

Ethanol induced NF-{kappa}B activation protects against cell injury in cultured rat gastric mucosal epithelium.

Ethanol is a well-established irritant inducing inflammation in gastric mucosa, but the effects at the cellular level remain unclear. This study investigates NF-kappaB activation in gastric mucosal cells by ethanol and assesses the effects of heat shock pretreatment in this ulcerogenic situation. Rat gastric mucosal epithelia were exposed to ethanol for different time periods. Heat shock was induced by incubating the cells at 42 degrees C for 1 h prior to the experiments. For evaluation of NF-kappaB activation, the nuclear fraction of the cell lysates was analyzed with an EMSA or an ELISA-base

Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta.

The vasorelaxant effects of sildenafil and T-1032 [methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate], two phosphodiesterase type 5 inhibitors, were examined in the isolated rat aorta. Sildenafil and T-1032, both of which have almost the same potency and selectivity regarding phosphodiesterase type 5 inhibitory activity, produced a similar, moderate, relaxation at 10(-10) to 10(-7) M (sildenafil: 66.8 +/- 13.7%; T-1032: 77.9 +/- 10.8% at 10(-7) M). However, sildenafil, but not T-1032, produced further relaxation at t

Possible new role for NF-kappaB in the resolution of inflammation.

Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Although much attention has focused on pro-inflammatory pathways that initiate inflammation, relatively little is known about the mechanisms that switch off inflammation and resolve the inflammatory response. The transcription factor NF-kappaB is thought to have a central role in the induction of pro-inflammatory gene expression and has attracted interest as a new target for the treatment of inflammatory disease. We show here that NF-kappaB activation in

Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that mult

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… In addition, vinyl sulfones were introduced by Bogyo et al. in 1997 [ 70 ] as a scaffold of irreversible inhibition, where it was suggested that the double bond of the vinyl sulfone moiety reacts with the hydroxyl on the threonine in the active site. … Given vinyl sulfones are one of the classes of proteasome inhibitors, this inverse correlation with activity indicates that multiple candidates bearing a vinyl carbon were selected for testing with a relatively low success rate, which is a hint that vinyl sulfones are a more challenging class from which …

[Determination of 29 per- and polyfluoroalkyl substances and 22 organophosphate esters and diester metabolites in human serum by high-throughput solid-phase extraction- ultra performance liquid chromatography- high resolution mass spectrometry].

Monitoring pollutants in human blood is a crucial basis for assessing human exposure levels and health risks. Per- and polyfluoroalkyl substances （PFAS）， organophosphate esters （OPEs）， and their diester metabolites （di-OPEs） are widespread environmental co-contaminants with significant toxic effects， making it crucial to monitor their internal human exposure levels. However， existing studies have predominantly investigated these substances in isolation， lacking comprehensive research that simultaneously quantifies PFAS， OPEs， and di-OPEs in human serum. Based on the pretreatment method of 96-w

In vitro evaluation of the anti-prionic activity of newly synthesized congo red derivatives.

"Transmissible Spongiform Encephalopathies" (TSE) are a group of degenerative progressive fatal disorders of the CNS, affecting both humans and animals. The main pathogenic event is the conversion of cellular prion protein from the normal, enzyme-sensitive (PrPsen), to the insoluble proteinase K-resistant isoform (PrPres). Since the new juvenile variant of Creutzfeldt-Jakob disease (vCJD) is probably due to the transmission of Bovine Spongiform Encephalopathy (BSE) prion protein to man, therapeutic and preventive compounds for animals and humans are urgently needed. Congo Red (benzidine-diazo-

Targeting the NLRP3 Inflammasome With Inhibitor MCC950 Prevents Aortic Aneurysms and Dissections in Mice.

Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3)-caspase-1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic ane

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/

Chronic inhibition of cGMP-specific phosphodiesterase 5 suppresses endoplasmic reticulum stress in heart failure.

BACKGROUND AND PURPOSE: Inhibition of the cGMP-specific phosphodiesterase 5 (PDE5) exerts profound beneficial effects on failing hearts. However, the mechanisms underlying the therapeutic effects of PDE5 inhibition on heart failure are unclear. The purpose of this study was to investigate whether PDE5 inhibition decreases endoplasmic reticulum (ER) stress, a key event in heart failure. EXPERIMENTAL APPROACH: Heart failure was induced by isoprenaline s.c. injection in Sprague-Dawley rats and transverse aortic constriction (TAC) in mice. PDE5 was inhibited with sildenafil. Heart function was de

Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer.

PURPOSE: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. METHODS: We performed molecular analysis of tumors from

cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function.

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neuro

Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension.

BACKGROUND: The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones. METHODS: Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezo

Sildenafil reduces polyuria in rats with lithium-induced NDI.

Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, β-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct

Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells.

Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin

Intrathecally injected morphine inhibits inflammatory paw edema: the involvement of nitric oxide and cyclic-guanosine monophosphate.

BACKGROUND: Morphine can inhibit inflammatory edema in experimental animals. The mechanisms and sites by which opioids exert this effect are still under debate. Since the spinal level is a site for modulation of the neurogenic component of inflammation, we investigated the effect of intrathecal (i.t.) administration of morphine, and the involvement of spinal nitric oxide (NO)/cyclic-guanosine monophosphate-GMP pathway in carrageenan (CG)-induced paw edema. METHODS: Male Wistar rats received i.t. injections of drugs (20 microL) 30 min before paw stimulation with CG (150 microg). Edema was meas

PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium.

BACKGROUND: The effects of protease-activated receptor-2 (PAR-2) stimulation on inflammation mechanisms of chronic rhinosinusitis (CRS) are still unknown. METHODS: PAR-2 receptor expression was investigated by immunohistochemistry and Taqman mRNA analysis in the mucosa of different rhinosinusitis entities. In primary nasal epithelial cell cultures, the function of PAR-2 and its ability to produce CXC, CC chemokines, and IL-6 were measured by calcium mobilization and stimulation tests. Inhibition tests were performed using cortisone, serine protease inhibitors, cysteine protease inhibitors, Pe

PLK1 inhibition enhances gemcitabine-induced apoptosis through PLK1-dependent ERK1/2-Bim and AKT1/Noxa signals in pancreatic cancer cells.

Polo-like kinase 1 (PLK1) is a critical regulator of many cell cycle events, which has been found to be associated with resistance to cytotoxic drugs. In the present study, we investigates how PLK1 regulates the sensitivity of pancreatic cancer cells to Gemcitabine (GEM) and its mechanism. We detected the expression of PLK1 in pancreatic cancer tissues and cell lines and study the effects of PLK1 and Gemcitabine on cell viability and apoptosis of GEM-resistant pancreatic cancer PANC-1 cells and Gemcitabine sensitive BxPC-3 cells; Using inhibitors or siRNA, we further investigate the effects of

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.

PURPOSE: We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis. PATIENTS AND METHODS: A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined a