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PubMed1999

Catalytic Upgrading of Fermentation-Derived Organic Acids.

The production of organic acids in low-cost, high-efficiency fermentation processes makes available a new route to chemical production from biomass. Because of their multiple functional groups and high reactivity, organic acids can undergo a variety of reactions that are effectively catalyzed by inorganic heterogeneous or homogeneous catalysts. Lactic acid and succinic acid, in particular, are approaching large-scale production via fermentation and show excellent promise as feedstocks for catalytic conversion routes such as hydrogenation, dehydration, or condensation. A number of catalytic conversion pathways of organic acids are potentially competitive with petroleum-based routes in the current economic environment, particularly when integrated into existing biomass/crop processing schemes. This article reviews some of the key reaction pathways available using fermentation-derived organic acids as feedstocks and presents recent results from the authors' lab on succinate hydrogenation to 1,4-butanediol and tetrahydrofuran. By a judicious choice of support properties and reaction conditions, it is possible to achieve yields of either of these two products in excess of 80%.

Journal Article↗

PubMed2000

Tyrosine kinase signalling in breast cancer: modulation of tyrosine kinase signalling in human breast cancer through altered expression of signalling intermediates.

The past decade has seen the definition of key signalling pathways downstream of receptor tyrosine kinases (RTKs) in terms of their components and the protein-protein interactions that facilitate signal transduction. Given the strong evidence that links signalling by certain families of RTKs to the progression of breast cancer, it is not surprising that the expression profile of key downstream signalling intermediates in this disease has also come under scrutiny, particularly because some exhibit transforming potential or amplify mitogenic signalling pathways when they are overexpressed. Reflecting the diverse cellular processes regulated by RTKs, it is now clear that altered expression of such signalling proteins in breast cancer may influence not only cellular proliferation (eg Grb2) but also the invasive properties of the cancer cells (eg EMS1/cortactin).

Adaptor Proteins, Signal Transducing↗

PubMed2004

Multiple functions of BMPs in chondrogenesis.

The ability of bone morphogenetic proteins (BMPs) to promote chondrogenesis has been investigated extensively over the past two decades. Although BMPs promote almost every aspect of chondrogenesis, from commitment to terminal differentiation is well known, the mechanisms of BMP action in discrete aspects of endochondral bone formation have only recently begun to be investigated. In this review, we focus on in vivo studies that have identified interactions between BMP signaling pathways and key downstream targets of BMP action in chondrogenesis. We also discuss evidence regarding the potential roles of BMP receptors in mediating distinct aspects of chondrogenesis, and studies investigating the intersection of BMP pathways with other pathways known to coordinate the progression of chondrocytes through the growth plate. These studies indicate that both Smad-dependent and -independent BMP pathways are required for chondrogenesis, and that BMPs exert essential roles via regulation of the Indian hedgehog (IHH)/parathyroid hormone-related protein (PTHrP) and fibroblast growth factor (FGF) pathways in the growth plate.

Animals↗

PubMed2006

Antennally mediated negative feedback regulation of pheromone production in the pine engraver beetle, Ips pini.

Bark beetles use monoterpenoid aggregation pheromones to coordinate host colonization and mating. These chemical signals are produced de novo in midgut cells via the mevalonate pathway, and pheromone production may be regulated by a negative feedback system mediated through the antennae. In this study, we explored the effect of antennectomy on pheromone production and transcript levels of key mevalonate pathway genes in juvenile hormone III-treated male pine engraver beetles, Ips pini (Say). Antennectomized males produced significantly greater amounts of pheromone than podectomized males and those with intact antennae. Likewise, mRNA levels of three mevalonate pathway genes important in pheromone biosynthesis were measured by quantitative real-time PCR and found to be induced to a greater extent with antennectomy, suggesting a transcriptional regulation of pheromone production.

Animals↗

PubMed2026

The association of cardiovascular health with new-onset pulmonary hypertension and the mediating role of proteomic signatures.

BACKGROUND: The cardiovascular health (CVH) metrics have been reported to play an important role in the development of noncommunicable chronic diseases, yet its link to pulmonary hypertension (PH) risk and the underlying biological mechanisms remain unclear. This study aimed to investigate the association of CVH with PH risk and elucidate the mediating role of plasma proteomic signatures. METHODS: A total of 279 220 participants without PH at enrollment of the UK Biobank were included. Cox regression was used to quantify the association between CVH and incident PH. Proteome-wide association analysis, mediation analysis, and functional enrichment analysis were conducted to identify protein mediators. Key hub proteins were further validated at the transcriptional level through quantitative polymerase chain reaction (qPCR) in an animal model of PH, as well as at the protein level, and by macrophage-specific knockdown of interleukin (IL)-6 and CCL4 to evaluate its impact on rat pulmonary artery smooth muscle cell (PASMC) migration and proliferation. RESULTS: Over a median 13.2-year follow-up, 1325 PH cases occurred. Compared to the lowest CVH, participants with moderate and high CVH had 59% [hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.33-0.49] and 82% (HR: 0.18; 95% CI: 0.14-0.23) lower risk, respectively. Proteomic analyses revealed that this association was significantly mediated by a distinct plasma protein signature. Pathway enrichment analysis indicates that proteins are significantly enriched in inflammatory/immune pathways, and key hub proteins were identified as participating in the central mechanism pathway. In the lung tissue of PH rat models, the mRNA and protein expression levels of IL-6 and C-C motif chemokine ligand 4 (CCL4) were significantly elevated. Furthermore, functional assays demonstrated that knockdown of IL-6 or CCL4 in macrophages significantly attenuated the migration and proliferation of rat PASMCs in vitro. CONCLUSION: High CVH level, defined by Life's Essential 8 (LE8), is significantly linked to a reduced risk of developing PH. This protective effect is primarily mediated by a proteomic signature, revealing the role of signaling pathways such as cytokine-cytokine receptor interaction in the prevention of PH.

Hypertension, Pulmonary↗

PubMed2006

Antiangiogenic drugs in non-small cell lung cancer treatment.

PURPOSE OF REVIEW: A promising therapeutic target is the vascular endothelial growth factor pathway - a key mediator of tumor angiogenesis - which is important in tumor growth, invasion, and metastasis. This review focuses on the available clinical data on drugs targeting the vascular endothelial growth factor - vascular endothelial growth factor receptor pathway in the treatment of non-small cell lung cancer. RECENT FINDINGS: The therapeutic value of inhibiting the vascular endothelial growth factor pathway has been demonstrated by using drugs that prevent vascular endothelial growth factor receptor binding and by using drugs that inhibit receptor activation. Two antiangiogenic drugs exemplify these mechanisms: bevacizumab (Avastin; Genentech, South San Francisco, California, USA), a humanized monoclonal antibody that acts by binding and neutralizing vascular endothelial growth factor; and ZD6474 (Zactima; AstraZeneca, Macclesfield, UK), a small-molecule inhibitor of vascular growth factor receptor and epidermal growth factor receptor tyrosine kinase activity. Recently, the first results of a large, phase III randomized clinical trial of bevacizumab in combination with platinum-based doublet chemotherapy have been reported in patients with nonsquamous non-small cell lung cancer. SUMMARY: The inhibition of tumor angiogenesis is a key therapeutic strategy that holds great promise for the advancement of metastatic lung cancer therapy. The combination of bevacizumab and conventional chemotherapy could offer a new therapeutic option in selected non-small cell lung cancer histotypes.

Angiogenesis Inhibitors↗

PubMed2006

Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose.

Hyperglycemia is a causal factor in the development of the vascular complications of diabetes. One of the biochemical mechanisms activated by excess glucose is the polyol pathway, the key enzyme of which, aldose reductase, transforms d-glucose into d-sorbitol, leading to imbalances of intracellular homeostasis. We aimed at verifying the effects of thiamine and benfotiamine on the polyol pathway, transketolase activity, and intracellular glucose in endothelial cells and pericytes under high ambient glucose. Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/liter) or high (28 mmol/liter) glucose, with or without thiamine or benfotiamine 50 or 100 mumol/liter. Transketolase and aldose reductase mRNA expression was determined by reverse transcription-PCR, and their activity was measured spectrophotometrically; sorbitol concentrations were quantified by gas chromatography-mass spectrometry and intracellular glucose concentrations by fluorescent enzyme-linked immunosorbent assay method. Thiamine and benfotiamine reduce aldose reductase mRNA expression, activity, sorbitol concentrations, and intracellular glucose while increasing the expression and activity of transketolase, for which it is a coenzyme, in human endothelial cells and bovine retinal pericytes cultured in high glucose. Thiamine and benfotiamine correct polyol pathway activation induced by high glucose in vascular cells. Activation of transketolase may shift excess glycolytic metabolites into the pentose phosphate cycle, accelerate the glycolytic flux, and reduce intracellular free glucose, thereby preventing its conversion to sorbitol. This effect on the polyol pathway, together with other beneficial effects reported for thiamine in high glucose, could justify testing thiamine as a potential approach to the prevention and/or treatment of diabetic complications.

Aldehyde Reductase↗

PubMed2002

Development of CAPS markers based on three key genes of the phenylpropanoid pathway in tea, Camellia sinensis (L.) O. Kuntze, and differentiation between assamica and sinensis varieties.

The genetic diversity of tea, Camellia sinensis (L.) O. Kuntze, including the two main cultivated sinensis and assamica varieties, was investigated based on PCR-RFLP analysis of PAL, CHS2 and DFR, three key genes involved in catechin and tannin synthesis and directly responsible for tea taste and quality. Polymorphisms were of two types: amplicon length polymorphism (ALP) due to the presence of indels in two introns of PAL and DFR, and point mutations detected after restriction of amplified fragments with appropriate enzymes. A progeny test showed that all markers segregated in a Mendelian fashion and that polymorphisms were exclusively co-dominant. CHS2, which belongs to a multi-gene family, allowed for greater variation than the single-copy PAL gene. Based on Nei's gene diversity index, var. sinensis was revealed to be more variable than var. assamica, and that a higher proportion of overall diversity resided within varieties as compared to between varieties. Even though no specific DNA profile was found for either tea varieties following any single PCR-RFLP analysis, a factorial correspondence analysis carried out on all genotypes and markers separated the tea samples into two distinct groups according to their varietal status. This reflects the large difference between var. sinensis and var. assamica in their polyphenolic profiles. The STS-based markers developed in this study will be very useful in future mapping, population genetics and fingerprinting studies of this important crop species and other Camellia species, as the primers have also proven successful in the three other subgenera of this genus.

Acyltransferases↗

PubMed2003

Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells.

The SK-N-MC neuroblastoma cell line, which expresses surface tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors TRAIL-R2 and TRAIL-R4, was used as a model system to examine the effect of TRAIL on key intracellular pathways involved in the control of neuronal cell survival and apoptosis. TRAIL induced distinct short-term (1-60 min) and long-term (3-24 h) effects on the protein kinase B (PKB)/Akt (Akt), extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), nuclear factor kappa B (NF-kappaB) and caspase pathways. TRAIL rapidly (from 20 min) induced the phosphorylation of Akt and ERK, but not of c-Jun NH2-terminal kinase (JNK). Moreover, TRAIL increased CREB phosphorylation and phospho-CREB DNA binding activity in a phosphatidylinositol 3-kinase (PI 3K)/Akt-dependent manner. At later time points (from 3 to 6 h onwards) TRAIL induced a progressive degradation of inhibitor of kappaB (IkappaB)beta and IkappaBepsilon, but not IkappaBalpha, coupled to the nuclear translocation of NF-kappaB and an increase in its DNA binding activity. In the same time frame, TRAIL started to activate caspase-8 and caspase-3, and to induce apoptosis. Remarkably, caspase-dependent cleavage of NF-kappaB family members as well as of Akt and CREB proteins, but not of ERK, became prominent at 24 h, a time point coincident with the peak of caspase-dependent apoptosis.

Apoptosis↗

PubMed2003

Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite.

Hyperoxia exposure induces capillary endothelial cell apoptosis in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy. Previous in vivo studies have shown that endothelial nitric oxide synthase (NOS3) and peroxynitrite are important mediators of the vaso-obliteration. Now we have investigated the relationship between hyperoxia, NOS3, peroxynitrite, and endothelial cell apoptosis by in vitro experiments using bovine retinal endothelial cells (BREC). We found that BREC exposed to 40% oxygen (hyperoxia) for 48 h underwent apoptosis associated with activation of caspase-3 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. Hyperoxia-induced apoptosis was associated with increased formation of nitric oxide, peroxynitrite, and superoxide anion and was blocked by treatment with uric acid, nitro-L-arginine methyl ester, or superoxide dismutase. Analyses of the phosphatidylinositol 3-kinase/Akt kinase survival pathway in cells directly treated with peroxynitrite revealed inhibition of VEGF- and basic FGF-induced activation of Akt kinase. These results suggest that hyperoxia-induced formation of peroxynitrite induces BREC apoptosis by crippling key survival pathways and that blocking peroxynitrite formation prevents apoptosis. These data may have important clinical implications for infants at risk of retinopathy of prematurity.

Animals↗

PubMed2006

EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-gamma: role of JAK/STAT1 signaling and implications for HIV-associated dementia.

Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV-infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-gamma (IFN-gamma) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in HIV-1-infected brains progressing to HAD. Recent reports suggest green tea-derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-gamma was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-gamma enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor, or those derived from STAT1-deficient mice, were largely resistant to the IFN-gamma-enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-gamma-enhanced neurotoxicity of gp120 and Tat by inhibiting JAK/STAT1 pathway activation. EGCG was also found to mitigate the neurotoxic properties of HIV-1 proteins in the presence of IFN-gamma in vivo. Taken together, these data suggest EGCG attenuates the neurotoxicity of IFN-gamma augmented neuronal damage from HIV-1 proteins gp120 and Tat both in vitro and in vivo. Thus EGCG may represent a novel natural copound for the prevention and treatment of HAD.

AIDS Dementia Complex↗

PubMed2002

PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival.

Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.

Animals↗

PubMed2006

Hydroxyquinol pathway for microbial degradation of halogenated aromatic compounds.

Several peripheral metabolic pathways can be used by microorganisms to degrade toxic aromatic compounds that are known to pollute the environment. Hydroxyquinol (1,2,4-trihydroxybenzene) is one of the central intermediates in the degradative pathway of a large variety of aromatic compounds. The present review describes the microorganisms involved in the degradative pathway, the key enzymes involved in the formation and splitting of the aromatic ring of (chloro)hydroxyquinol as well as the central intermediates formed. An attempt was also made to provide some estimation for genetic basis of the hydroxyquinol pathway.

Bacteria↗

PubMed2005

The molecular pathogenetic role of cell adhesion in endocrine neoplasia.

It is becoming increasingly evident that cell adhesion is an important determinant of organised growth and the maintenance of architectural integrity. Indeed, reduced adhesiveness between cells and with the extracellular matrix is a hallmark of neoplastic growth. In neuroendocrine tissues, neural cell adhesion molecule is implicated in modulating cell growth, migration, and differentiation. This review will focus on the molecular pathways involving key growth factor receptors that govern normal adhesive forces. The extent to which disruption of these adhesive forces contributes to the tumorigenic process in neuroendocrine tissues will be highlighted. Validation of the functional relevance of these adhesive pathways will be discussed in light of targeted pharmacotherapeutic studies that are unmasking novel approaches to the treatment of neuroendocrine tumours.

Cell Adhesion↗

PubMed2005

Nitric oxide and mitochondrial biogenesis: a key to long-term regulation of cellular metabolism.

Mitochondria, the site of oxidative energy metabolism in eukariotic cells, are a highly organised structure endowed with different enzymes and reactions localized in discrete membranes and aqueous compartments. Mitochondrial function is regulated in complex ways by several agonists and environmental conditions, through activation of specific transcription factors and signalling pathways. A key player in this scenario is nitric oxide (NO). Its binding to cytochrome c oxidase in the mitochondrial respiratory chain, which is reversible and in competition with oxygen, plays a role in acute oxygen sensing and in the cell response to hypoxia. Evidence of the last two years showed that NO has also long-term effects, leading to biogenesis of functionally active mitochondria, that complement its oxygen sensing function. Mitochondrial biogenesis is triggered by NO through activation of guanylate cyclase and generation of cyclic GMP, and yields formation of functionally active mitochondria. Thus, the combined action of NO at its two known intracellular receptors, cytochrome c oxidase and guanylate cyclase, appears to play a role in coupling energy generation with energy demand. This may explain why dysregulation of the NO signalling pathway is often associated with the pathogenesis of metabolic disorders.

Animals↗

PubMed2004

LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution.

The Wnt signaling pathway plays key roles in both embryogenesis and tumorigenesis. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6), a novel member of the expanding LDL receptor family, functions as an indispensable co-receptor for the Wnt signaling pathway. Although the role of LRP6 in embryonic development is now well established, its role in tumorigenesis is unclear. We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues. Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased. This is accompanied by a significant increase in Wnt/beta-catenin signaling and cell proliferation. Finally, we demonstrate that LRP6 expression promotes tumorigenesis in vivo. These results thus indicate that LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling.

Animals↗

PubMed2004

Human T lymphotropic virus type-1 p30II alters cellular gene expression to selectively enhance signaling pathways that activate T lymphocytes.

BACKGROUND: Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma and is implicated in a variety of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13II and p30II, which are incompletely defined in the virus life cycle or HTLV-1 pathogenesis. Proviral clones of the virus with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. Exogenous expression of p30II differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and represses tax/rex RNA nuclear export. RESULTS: Herein, we further characterized the role of p30II in regulation of cellular gene expression, using stable p30II expression system employing lentiviral vectors to test cellular gene expression with Affymetrix U133A arrays, representing approximately 33,000 human genes. Reporter assays in Jurkat T cells and RT-PCR in Jurkat and primary CD4+ T-lymphocytes were used to confirm selected gene expression patterns. Our data reveals alterations of interrelated pathways of cell proliferation, T-cell signaling, apoptosis and cell cycle in p30II expressing Jurkat T cells. In all categories, p30II appeared to be an overall repressor of cellular gene expression, while selectively increasing the expression of certain key regulatory genes. CONCLUSIONS: We are the first to demonstrate that p30II, while repressing the expression of many genes, selectively activates key gene pathways involved in T-cell signaling/activation. Collectively, our data suggests that this complex retrovirus, associated with lymphoproliferative diseases, relies upon accessory gene products to modify cellular environment to promote clonal expansion of the virus genome and thus maintain proviral loads in vivo.

Apoptosis↗

PubMed1998

Stress-activated kinases regulate protein stability.

Proteasome inhibitors have been used to demonstrate that many proteins of the signal transduction pathways are regulated by degradation via the ubiquitin-proteasome pathway. The key question is what events target specific proteins for ubiquitination at one time and prevent ubiquitination at other times? In this review, we develop the notion that there is a direct relationship between the phosphorylation/dephosphorylation cascade of the signal transduction pathways and the targeting of the regulatory proteins for ubiquitination. We present examples where phosphorylation appears to alter the interaction between the targeting systems and the substrate by modifying the targeting system, the substrate, or both. These interacting systems are seen in the response of p53, c-jun and ATF-2 in cells subjected to stress or DNA damage and to the normal regulated response in a variety of pathways including the IkappaB-NFkappaB and JAK-STAT pathways. The interweaving of the two post-translational networks, phosphorylation and ubiquitination, provides a powerful insight into global regulatory control pathways.

Animals↗