Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition.

Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells.

Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase.

Endocrine therapy resistance is a primary cause of clinical breast cancer treatment failure. The p38 mitogen activated protein kinase (MAPK) signaling pathway is known to promote ligand independent tumor growth and resistance to endocrine therapy. In this study, we investigated the therapeutic potential of the p38 inhibitor RWJ67657 in the treatment of tamoxifen resistant MDA-MB-361 cells.

Inhibition of p38-MAPK alters SRC coactivation and estrogen receptor phosphorylation.

The p38 mitogen activated protein kinase pathway (MAPK) is known to promote cell survival, endocrine therapy resistance and hormone independent breast cancer cell proliferation. Therefore, we utilized the novel p38 inhibitor RWJ67657 to investigate the relevance of targeting this pathway in the ER (+) breast cancer cell line MCF-7. Our results show that RWJ67657 inhibits both basal and estrogen stimulated phosphorylation of p38α, resulting in decreased activation of the downstream p38α targets hsp27 and MAPAPK.

Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats.

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo.

Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.

Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling.

Osteogenic activity of locally applied small molecule drugs in a rat femur defect model.

The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT) and histomorphometry.

p38 MAPK inhibition reduces diabetes-induced impairment of wound healing.

In healthy tissue, a wound initiates an inflammatory response characterized by the presence of a hematoma, infiltration of inflammatory cells into the wound and, eventually, wound healing. In pathological conditions like diabetes mellitus, wound healing is impaired by the presence of chronic nonresolving inflammation. p38 mitogen-activated protein kinase (MAPK) inhibitors have demonstrated anti-inflammatory effects, primarily by inhibiting the expression of inflammatory cytokines and regulating cellular traffic into wounds.

Reducing post-surgical adhesions utilizing a drug-enhanced device: sodium carboxymethylcellulose aqueous gel/poly(p-dioxanone) and Tranilast.

Post-surgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed to reduce tissue trauma seen with open procedures. However, despite surgeons' meticulous techniques and the use of such barriers, adhesion formation remains a serious clinical problem, creating complications that cost the health care system over $1 billion annually.

Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase.

The activity of nuclear transcription factors is often regulated by specific kinase-signaling pathways. We have previously shown that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) stimulates activator protein-1 activity through the p38 mitogen-activated protein kinase (MAPK). Here, we show that DDT and its metabolites also stimulate the transcriptional activity of cyclic adenosine monophosphate response element-binding protein and Elk1 and potentiate gene expression through cyclic adenosine monophosphate and hypoxia response elements.

Tranilast: a pharmaceutical candidate for reduction of adhesions using a novel approach.

Postsurgical adhesion formation has numerous deleterious side effects in a wide variety of surgical settings. Physical barriers used together with laparoscopy were developed in hopes of reducing the tissue trauma seen with open procedures and separating tissues during the critical time of healing to reduce adhesion formation. Despite meticulous techniques by surgeons and the availability of barriers, adhesion formation remains a serious problem, with more than $1 billion spent annually on complications arising from adhesions.

Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection.

We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T.

Reduction of post-surgical adhesion formation with tranilast.

Background: Preclinical studies using the rabbit sidewall and double uterine horn models were used to assess time and dose response of tranilast delivered via subcutaneous pump, p.o., or as an intraperitoneal bolus in viscoelastic gels as well as an intraperitoneal biodegradable poly(p-dioxanone) fiber in reducing adhesions compared to vehicle controls.

Inhibitors of unactivated p38 MAP kinase.

Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo.

A multiplexed proteomics approach to differentiate neurite outgrowth patterns.

We report here a method for proteomics pattern discovery by utilizing a self-organizing map approach to analyze data obtained from a novel multiplex iTRAQ proteomics method. Through the application of this technique, we were able to delineate the early molecular events preceding dorsal root ganglia neurite outgrowth induced by either nerve growth factor (NGF) or an immunophilin ligand, JNJ460. Following pattern analysis we discovered that each neurotrophic agent promoted mostly distinct increases in protein expression with few overlapping patterns.

HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation.

The human immunodeficiency virus (HIV) has been reported to target noninfected CD4 and CD8 cells for destruction. This effect is manifested in part through up-regulation of the death receptor Fas ligand (FasL) by HIV-1 negative factor (Nef), leading to bystander damage. However, the signal transduction and transcriptional regulation of this process remains elusive.

A novel role for the immunophilin FKBP52 in copper transport.

FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase (PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library.

Suppression of HIV-1 viral replication and cellular pathogenesis by a novel p38/JNK kinase inhibitor.

Objective: To analyze a novel compound, which inhibits serine-threonine protein kinase p38, for its possible bioactivity against HIV-1 infection.

Methods: Proteins involved in cellular signal transduction pathways represent a novel class of host therapeutic targets for infectious diseases. In this regard the serine/threonine kinase p38 MAPK, a member of the mitogen-activated protein (MAP) kinase superfamily of signal transduction molecules may play an important role in HIV-1 infection.

Imidazopyrimidines, potent inhibitors of p38 MAP kinase.

The MAP kinase p38 is implicated in the release of the pro-inflammatory cytokines TNF-alpha and IL-1 beta. Inhibition of cytokine release may be a useful treatment for inflammatory conditions such as rheumatoid arthritis and Crohn's disease. A novel series of imidazopyrimidines have been discovered that potently inhibit p38 and suppress the production of TNF-alpha in vivo.

Opposing roles of serine/threonine kinases MEKK1 and LOK in regulating the CD28 responsive element in T-cells.

T-cell activation requires signals from both the T-cell receptor (TcR) and other co-stimulatory molecules such as CD28. TcR- and CD28-mediated signals are integrated during T-cell activation resulting in the expression of cytokine genes such as interleukin-2 (IL-2). An enhancer element (CD28RE) of the IL-2 gene specifically responsive to CD28 signals has been previously identified and characterized.