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PubMed1999

Developmental pathways: Sonic hedgehog-Patched-GLI.

Developmental pathways are networks of genes that act coordinately to establish the body plan. Disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Environmental exposures can be associated with poor pregnancy outcomes, including dysmorphic offspring or children with a variety of diseases. An important goal of environmental science should be reduction of these poor outcomes. This will require an understanding of the genes affected by specific exposures and the consequence of alterations in these genes or their products, which in turn will require an understanding of the pathways critical in development. The ligand Sonic hedgehog, the receptors Patched and Smoothened, and the GLI family of transcription factors represent one such pathway. This pathway illustrates several operating principles important in the consideration of developmental consequences of environmental exposures to toxins.

Abnormalities, Drug-Induced↗
PubMed2006

Emerging drugs for hepatocellular carcinoma.

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/beta-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.

Animals↗
PubMed2003

Akt1 protects against inflammatory microglial activation through maintenance of membrane asymmetry and modulation of cysteine protease activity.

In several cell systems, protein kinase B (Akt1) can promote cell growth and development, but the "antiapoptotic" pathways of this kinase that may offer protection against cellular inflammatory demise have not been defined. Given that early cellular membrane phosphatidylserine exposure is a critical component of apoptosis, we investigated the role of Akt1 during neuronal apoptotic injury. By employing differentiated SH-SY5Y neuronal cells that overexpress a constitutively active form of Akt1 (myristoylated Akt1), free radical-induced cell injury was assessed through trypan blue dye exclusion, DNA fragmentation, membrane phosphatidylserine exposure, protein kinase B phosphorylation, cysteine protease activity, and mitochondrial membrane potential. Membrane phosphatidylserine exposure was both necessary and sufficient for microglial activation, insofar as cotreatment with an antiphosphatidylserine receptor-neutralizing antibody could prevent microglial activity following neuronal loss of membrane asymmetry. Furthermore, expression of myristoylated Akt1 not only prevented cell injury through the prevention of membrane phosphatidylserine exposure and genomic DNA fragmentation but also inhibited microglial activation and proliferation that required the inhibition of caspase 9-, caspase 3-, and caspase 1-like activities linked to cytochrome c release. Interestingly, Akt1 modulation of membrane phosphatidylserine exposure was primarily through caspase 1 activity. Removal of Akt1 activity abolished neuronal protection, suggesting that Akt1 functions as a critical pathway for the maintenance of cellular integrity and the prevention of phagocytic cellular removal during neurodegenerative insults.

Cell Membrane↗
PubMed1999

[Project graph technique for time management in abdominal ultrasound evaluations].

PURPOSE: German insurance companies are cutting down the time required for ultrasound examinations. To determine the minimal examination time to perform an ultrasound examination a project graph technique was applied. MATERIALS AND METHODS: Time measurements of abdominal ultrasound examinations were performed by two independent observers. The different jobs for the performance of an ultrasound examination were determined and the critical pathway method applied. The total available time for abdominal ultrasound examinations (leeway) was determined, the minimal time to perform each job was measured and the critical time required for the procedure was calculated. RESULTS: 14 different jobs were identified to complete one abdominal ultrasound examination. The project graph displayed the shortest possible time of 24 minutes to perform an ultrasound examination. The pure ultrasound exam without colour Doppler examination was 6 minutes ("hands on the ultrasound probe"). The jobs performed by the physician were fully within the critical period. In consequence, the physician had no leeway or time lag in relation to a total time of 24 minutes for an ultrasound examination, whereas by contrast the nurse has a total leeway of 7.5 minutes. CONCLUSIONS: The applied project graph technique is an effective instrument for the purpose of quality management for hospitals as well as in private practice. The workflow and actions necessary to perform a treatment or examination can be analysed. Human resources management and cost planning should be performed on the basis of project graphs.

Abdomen↗
PubMed2006

Two signaling pathways regulate the expression and secretion of a neuropeptide required for long-term facilitation in Aplysia.

Activation of several signaling pathways contributes to long-term synaptic plasticity, but how brief stimuli produce coordinated activation of these pathways is not understood. In Aplysia, the long-term facilitation (LTF) of sensory neuron synapses by 5-hydroxytryptamine (serotonin; 5-HT) requires the activation of several kinases, including mitogen-activated protein kinase (MAPK). The 5-HT-enhanced secretion of the sensory neuron-specific neuropeptide sensorin mediates the activation of MAPK. We find that stimulus-induced activation of two signaling pathways, phosphoinositide 3-kinase (PI3K) and type II protein kinase A (PKA), regulate sensorin secretion and responses. Treatment with 5-HT produces a rapid increase in sensorin synthesis, especially at varicosities, which precedes the secretion of sensorin. PI3K inhibitor and rapamycin block LTF and the rapid synthesis of sensorin at varicosities even in the absence of sensory neuron cell bodies. Secretion of the newly synthesized sensorin from the varicosities and activation of the autocrine responses of sensorin to produce LTF require type II PKA interaction with AKAPs (A-kinase anchoring proteins). Thus, long-term synaptic plasticity is produced when multiple signaling pathways that are important for regulating distinct cellular functions are activated in a specific sequence and recruit the secretion of a neuropeptide to activate additional critical pathways.

Animals↗
PubMed2026

Systematic identification of germ granule proteins reveals specialized roles in RNAi and small RNA inheritance.

Biomolecular condensates, such as germ granules, organize RNAi pathways critical for fertility and genome regulation. However, the protein composition and functional contributions of these condensates remain poorly defined. Here, we applied TurboID proximity labeling to the Caenorhabditis elegans germ granule protein SIMR-1, integrating mass spectrometry with genetic screening, CRISPR-based tagging, and small RNA sequencing. This systematic approach identified several previously uncharacterized germ granule proteins that contribute to fertility, germline immortality, exogenous RNAi, and transgenerational inheritance. Small RNA sequencing of 21 mutants revealed broad and class-specific defects in siRNA and miRNA biogenesis, with distinct factors associated with defects in WAGO-class 22G-RNAs, CSR-class 22G-RNAs, or histone-directed small RNAs. Among these, we identified PINT-1, a highly disordered protein that directly interacts with and is recruited to germ granules by the PIWI Argonaute PRG-1. PINT-1 is required for piRNA-dependent and -independent secondary siRNA biogenesis and germline development. Comparative genomics revealed that PINT-1 has coevolved with PRG-1 across clade V nematodes, with a conserved structured N terminus and a rapidly diverging repeat-rich intrinsically disordered region. Together, our findings expand the germ granule proteome and reveal how distinct condensate components contribute to specialized functions within the small RNA pathways, while highlighting an evolutionarily coadapted PIWI interactor critical for siRNA biogenesis.

Animals↗
PubMed2005

Hepatocellular carcinoma: molecular pathways and new therapeutic targets.

Hepatocellular carcinoma is often diagnosed at an advanced stage, when it is not amenable to curative therapies. There is no effective chemotherapy. Advances in cancer biology suggest that a limited number of pathways are responsible for initiating and maintaining dysregulated cell proliferation, which is the major cellular alteration responsible for the cancer phenotype. New treatments in development target several of these critical pathways, including agents targeting the receptor tyrosine kinase pathways, the Wnt/beta-catenin signaling pathway, the ubiquitin/proteasome degradation pathway, the epigenetic DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, and telomerase. Several of these approaches hold significant promise for improving the long-term outcome of patients with advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, these approaches must be coupled with new strategies for halting or reversing the progression of chronic liver disease.

Animals↗
PubMed2002

Targeting the molecular pathophysiology of gastrointestinal stromal tumors with imatinib. Mechanisms, successes, and challenges to rational drug development.

The development of imatinib as molecularly targeted therapy for GIST represents an important case study of rational drug development. It is a paradigm of how the molecular understanding of a cancer has resulted in a new effective therapy that targets the critical pathway upon which the GIST cells were dependent: the uncontrollably active KIT signaling pathway. Unresectable or metastatic GISTs have traditionally exhibited a rapid and fatal clinical course, with no evidence of benefit from any standard cytotoxic chemotherapy. The identification of KIT activation as a critical factor in the pathogenesis of GIST led to the search for a new type of therapeutic compound to serve as a KIT inhibitor and to interfere with the constitutive phosphorylation of the KIT kinase in GIST cells. Clarification of the molecular genetic pathophysiology of GIST and the role of KIT activation in this disease, therefore, has not only enabled improved diagnosis and differentiation of GIST from other mesenchymal neoplasms but has also been key in identifying new targeted strategies for therapeutic intervention. The improved understanding of the molecular pathophysiology of GIST, a disease that was previously untreatable with any available systemic therapy, has led to the development of imatinib, a well-tolerated agent that can inhibit the dysregulated KIT signaling pathways in GIST. Imatinib represents the first (and currently the only) effective systemic therapy for patients with unresectable GIST. Imatinib therapy can induce objective responses and stabilization of disease and can provide clinical benefit in the majority of GIST patients treated with the drug. Other strategies are beginning to be explored, such as the use of imatinib earlier the in course of GIST (e.g., as adjuvant therapy after definitive surgical resection of early-stage disease). Integration of signal transduction inhibitors into the armamentarium of cancer therapeutics will undoubtedly continue based on this important paradigm of GIST.

Antineoplastic Agents↗
PubMed2004

PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development.

The identification of new signaling pathways critical for cardiac morphogenesis will contribute to our understanding of congenital heart disease (CHD), which remains a leading cause of mortality in newborn children worldwide. Signals mediated by semaphorin ligands and plexin receptors contribute to the intricate patterning of axons in the central nervous system. Here, we describe a related signaling pathway involving secreted class 3 semaphorins, neuropilins, and a plexin receptor, PlexinD1, expressed by endothelial cells. Interruption of this pathway in mice results in CHD and vascular patterning defects. The type of CHD caused by inactivation of PlexinD1 has previously been attributed to abnormalities of neural crest. Here, we show that this form of CHD can be caused by cell-autonomous endothelial defects. Thus, molecular programs that mediate axon guidance in the central nervous system also function in endothelial cells to orchestrate critical aspects of cardiac morphogenesis.

Animals↗
PubMed1997

Regulation of proliferation and apoptosis by Ras and Rho GTPases through specific phospholipid-dependent signaling.

Small GTPases are molecular switches that control signaling pathways critical for diverse cellular functions. Recent evidence indicates that multiple effector molecules can be activated by small GTPases. As a result, complex biological processes such as cell proliferation and apoptosis are turned on. Thus, rather than a single linear pathway from the membrane to the nucleus, the integration of complementary signals is required for these events to occur. In fact, the coordinated activation of small GTPases may constitute some of the critical modulators of those signals triggering either proliferation or cell death. In addition to the activation of specific kinases cascades, phospholipid-derived messengers are candidates to compose some of the most critical elements associated to regulation of signaling cascades capable of discerning among life and death. Both proliferation and apoptosis needs competence and progression signals. Phospholipase D and sphingomyelinase may be important players in this decision-maker step.

Animals↗
PubMed2004

A systems approach to discovering signaling and regulatory pathways--or, how to digest large interaction networks into relevant pieces.

In the post-genomic era, the first step in any study of protein function is a homology search against the complete genome sequence of the organism of interest. By analogy, if we also wish to elucidate the cadre of signaling and regulatory pathways in the cell, an extremely powerful first step is to construct a complete network of protein-protein and transcriptional interactions and then search through this network to identify critical pathways in a top-down fashion. Like genomic sequence, the molecular interaction network provides a broad foundation for more directed studies to follow. We illustrate this strategy using a large network of 12,232 interactions in yeast. A variety of applications are discussed, including screening the network to identify pathways responsible for gene expression changes observed in galactose-induced cells, and identifying groups of interacting proteins that are essential (by phenotypic assay) for the cellular response to DNA damage.

Cell Physiological Phenomena↗
PubMed2002

Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12(I).

Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4(+) T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12(I) is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. To test whether p12(I) modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-kappaB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12(I)-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12(I) specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-kappaB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanediylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12(I)-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-gamma and LAT (linker for activation of T cells) did not affect p12(I)-induced NFAT activity. Importantly, p12(I) functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12(I) in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.

Calcium↗
PubMed2003

Receptor tyrosine kinase-GPCR signal complexes.

The formation of complexes between growth factor receptors and members of a family of G-protein-coupled receptors whose natural ligands are S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) represents a new signalling entity. This receptor complex allows for integrated signalling in response to growth factor and/or S1P/LPA and provides a mechanism for more efficient activation (due to integrated close-proximity signalling from both receptor classes) of the p42/p44 MAPK (mitogen-activated protein kinase) pathway. This article provides information on the molecular events at the interface between receptor tyrosine kinases and S1P/LPA receptors. Examples include the PDGF (platelet-derived growth factor)-induced tyrosine phosphorylation of G(i)alpha, released upon S1P(1) receptor activation, which is required for initiation of the p42/p44 MAPK pathway. Critical to this event is the formation of endocytic vesicles containing functionally active PDGFbeta receptor-S1P(1) receptor complexes, which are internalized and relocated with components of the p42/p44 MAPK pathway. We also report examples of cross-talk signal integration between the Trk A (tropomyosin receptor kinase A) receptor and the LPA(1) receptor in terms of the NGF (nerve growth factor)-dependent regulation of the p42/p44 MAPK pathway. NGF induces recruitment of the LPA(1) receptor to the nucleus (delivery might be Trk A-dependent), whereupon the LPA(1) receptor may govern gene expression via novel nuclear signalling processes.

Cell Line↗
PubMed2005

Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice.

Chemoprevention has come of age as an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable of intervening at more than one critical pathway in the carcinogenesis process will have greater advantage over other single-target agents. Pomegranate fruit extract (PFE) derived from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. Pomegranate fruit was extracted with acetone and analyzed based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and found to contain anthocyanins, ellagitannins and hydrolyzable tannins. We evaluated whether PFE possesses antitumor-promoting effects. We first determined the effect of topical application of PFE to CD-1 mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of PFE (2 mg/mouse) 30 min prior to TPA (3.2 nmole/mouse) application on mouse skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in skin edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and protein expression of ODC and cyclooxygenase-2. We also found that topical application of PFE resulted in inhibition of TPA-induced phosphorylation of ERK1/2, p38 and JNK1/2, as well as activation of NF-kappaB and IKKalpha and phosphorylation and degradation of IkappaBalpha. We next assessed the effect of skin application of PFE on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated CD-1 mouse. The animals pretreated with PFE showed substantially reduced tumor incidence and lower tumor body burden when assessed as total number of tumors per group, percent of mice with tumors and number of tumors per animal as compared to animals that did not receive PFE. In TPA-treated group, 100% of the mice developed tumors at 16 weeks on test, whereas at this time in PFE-treated group, only 30% mice exhibited tumors. Skin application of PFE prior to TPA application also resulted in a significant delay in latency period from 9 to 14 weeks and afforded protection when tumor data were considered in terms of tumor incidence and tumor multiplicity. The results of our study provide clear evidence that PFE possesses antiskin-tumor-promoting effects in CD-1 mouse. Because PFE is capable of inhibiting conventional as well as novel biomarkers of TPA-induced tumor promotion, it may possess chemopreventive activity in a wide range of tumor models. Thus, an in-depth study to define active agent(s) in PFE capable of affording antitumor-promoting effect is warranted.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2025

Regulation of airway fumarate by host and pathogen promotes S. aureus pneumonia.

Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.

Journal Article↗
PubMed2003

IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction.

Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, whereas ischemia and direct inflammation of the heart can precipitate transient or permanent impairments in contractility. Many of the insults that trigger contractile dysfunction also activate the innate immune system. Activation of the innate immune response to infection is coordinated by the conserved Toll/interleukin-1 (IL-1) signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, although their function is unknown. The hypotheses that Toll/IL-1 signaling occurs in the heart and that intact pathway function is required for contractile dysfunction after different insults were tested. Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate in the heart, indicating that the function of this pathway is not limited to immune system tissues. Moreover, hearts lacking IRAK1 exhibit impaired LPS-triggered downstream signal transduction. Hearts from IRAK1-deficient mice also resist acute LPS-induced contractile dysfunction. Finally, IRAK1 inactivation enhances survival of transgenic mice that develop severe myocarditis and lethal heart failure. Thus the Toll/IL-1 pathway is active in myocardial tissue and interference with pathway function, through IRAK1 inactivation, may represent a novel strategy to protect against cardiac contractile dysfunction.

Acute Disease↗
PubMed1982

Perifornical fiber system mediates VMH electrically-induced suppression of feeding.

Fiber pathways mediating the cessation of food ingestion during continuous low-level electrical stimulation of the ventromedial region of the hypothalamus (VMH) were appraised in food-deprived male rats using knife cuts. Parasagittal knife cuts in the medial perifornical area of the hypothalamus produced much larger increases in threshold current intensities for the inhibition of feeding than did cuts in the lateral perifornical hypothalamus. These findings indicate that fiber pathways critical to the inhibitory feeding effect of continuous VMH electrical stimulation traverse the perifornical hypothalamus but not the lateral hypothalamus. A comparison of these and other results demonstrates an anatomical similarity between the fiber pathways mediating VMH electrically-induced inhibition of feeding and hypothalamic hyperphagia following lesions or knife cuts. The nature of the inhibitory feeding effect of VMH electrical stimulation is also addressed and behavioral observations strongly supportive of a specific anorectic effect produced by the stimulation are reported.

Animals↗
PubMed2006

Long-lasting reductions of ethanol drinking, enhanced ethanol-induced sedation, and decreased c-fos expression in the Edinger-Westphal nucleus in Wistar rats exposed to the organophosphate chlorpyrifos.

Intermittent or continuous exposure to a wide variety of chemically unrelated environmental pollutants might result in the development of multiple chemical intolerance and increased sensitivity to drugs of abuse. Interestingly, clinical evidence suggests that exposure to organophosphates might be linked to increased ethanol sensitivity and reduced voluntary consumption of ethanol-containing beverages in humans. The growing body of clinical and experimental evidence emerging in this new scientific field that bridges environmental health sciences, toxicology, and drug research calls for well-controlled studies aimed to analyze the nature of the neurobiological interactions of drugs and pollutants. Present study specifically evaluated neurobiological and behavioral responses to ethanol in Wistar rats that were previously exposed to the pesticide organophosphate chlorpyrifos (CPF). In agreement with clinical data, animals pretreated with a single injection of CPF showed long-lasting ethanol avoidance that was not secondary to altered gustatory processing or enhancement of the aversive properties of ethanol. Furthermore, CPF pretreatment increased ethanol-induced sedation without altering blood ethanol levels. An immunocytochemical assay revealed reduced c-fos expression in the Edinger-Westphal nucleus following CPF treatment, a critical brain area that has been implicated in ethanol intake and sedation. We hypothesize that CPF might modulate cellular mechanisms (decreased intracellular cAMP signaling, alpha-7-nicotinic receptors, and/or cerebral acetylcholinesterase inhibition) in neuronal pathways critically involved in neurobiological responses to ethanol.

Alcohol Drinking↗