Dysregulated recruitment of leukocytes into the intestine is a characteristic feature of IBD. Several families of molecules regulate the influx of these cells into sites of inflammation within the gastrointestinal tract. Interference with molecules that mediate the formation of stable bonds (integrins) with their endothelial ligands has already shown efficacy in the clinics. Antibodies that target participant molecules have been approved by the US Federal Drug Administration for use in Crohn’s, multiple sclerosis (MS) (i.e. natalizumab) and psoriasis (i.e. efalizumab). A more recent additional family of drugs, which might also interfere with lymphocyte traffic (i.e. shingosine-1-phosphate receptor agonists: fingolimod) is in clinical use for MS and just recently entered the clinical trial stage for ulcerative colitis. In the present review we discuss basic aspects of clinically relevant molecules and compile the clinical studies that support the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in IBD.
adhesion molecules; chemokines; Crohn’s disease; integrins; sphingosine1-phosphate; ulcerative colitis
Radiation nephropathy and other normal tissue radiation injuries can be successfully mitigated, and also treated, by antagonists of the renin-angiotensin system (RAS). This implies a mechanistic role for that system in radiation nephropathy, yet no evidence exists to date of activation of the RAS by irradiation. RAS antagonists, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are the standard of care in the treatment of subjects with other chronic progressive kidney diseases, in which they exert benefit by reducing both glomerular and tubulo-interstitial injury. These drugs are likely to act in a similar way to mitigate radiation nephropathy.
radiation injuries; radiation nephropathy; renin-angiotensin system; angiotensins; captopril; mesangiolysis
Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. This area of research has seen a rapid increase in interest in the past decade, with the structurally diverse natural products-derived compounds at its forefront. These secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.
Histone acetylation; histone deacetylases; histone acetyltransferases; natural products; secondary metabolites
The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders.
Glia; Fronto-limbic; Depression; Glutamate; Postmortem
Effective systemic treatment of pancreatic cancer remains a major challenge, with progress hampered by drug resistance and treatment related toxicities. Currently available cytotoxic agents as monotherapy or in combination have provided only a modest survival benefit for patients with advanced disease. Disappointing phase III results with gemcitabine-based combinations in patients with advanced pancreatic cancer might be related to poor efficacy of systemic therapies in unselected patients. Future research strategies should prioritize identification of predictive markers through pharmacogenetic investigations. The individualization of patient treatment through pharmacogenetics may help to improve outcome by maximizing efficacy whilst lowering toxicity. This review provides an update on the pharmacogenetics of pancreatic cancer treatment and its influence on treatment benefits and toxicity.
Pancreatic cancer; pharmacogenetics; chemotherapy
The Forkhead Box O (Foxo) proteins represent an evolutionarily conserved family of transcription factors that play an important role in regulating processes including metabolism, longevity, and cell death/survival. How is it that a single transcription factor can initiate such divergent cellular responses? We will review the evidence that specific patterns of post-translational modifications play a key role in directing Foxo into various transcriptional readouts. This regulation appears to take on a two tiered regulatory model; with a group of well defined post-translational modifications regulating nuclear localization and transcriptional activity while a second set of modifications regulate the transcriptional specificity of Foxo.
Foxo; post-translational modifications; phosphorylation; acetylation; ubiquitination
The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood. MicroRNAs (miRNAs) have been proved to act as key regulators of the post-transcriptional regulation of genes, which involve in a wide array of biological processes including tumorigenesis. The altered expressions of miRNAs are associated with poor clinical outcome of patients diagnosed with a variety of tumors. Therefore, emerging evidence strongly suggest that miRMAs play critical roles in tumor development and progression. Emerging evidence also suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, drug resistance, and metastasis. Moreover, miRNAs such as let-7, miR-21, miR-22, miR-34, miR-101, miR-146a, and miR-200 have been found to be associated with CSC phenotype and function mediated through targeting oncogenic signaling pathways. In this article, we will discuss the role of miRNAs in the regulation of CSC phenotype and function during tumor development and progression. We will also discuss the potential role of naturally occurring agents (nutraceuticals) as potent anti-tumor agents that are believed to function by targeting CSC-related miRNAs.
CSCs; miRNAs; natural agents
The Janus kinases (or Jak kinases) mediate cytokine and growth factor
signal transduction. Acquired or inherited Jak mutations can result in
dysregulation of Jak-mediated signal transduction and can be critical to disease
acquisition in neoplasias including acute myeloid, acute lymphoblastic and acute
megakaryoblastic leukemias, and in rare X-linked severe combined
immunodeficiency. The discovery of an acquired Jak2 point mutation, V617F, in
significant numbers of patients with classical myeloproliferative disorders has
increased the interest in development of Jak2-specific tyrosine kinase
inhibitors and consequently there are now over 20 publically available
structures of Jak kinase domains that describe all four family members, Jak1,
Jak2, Jak3, and Tyk2. Here we review the recent advances in understanding the
druggable structure and function of the Jak family, with a focus on the
structural biology of the Jak kinase domain. We will discuss how these advances
impact the development of Jak-targeted therapeutics.
Jak kinase; Crystal structure; CP-690; 550; Jak2-V617F; Kinase inhibitor
Nontoxic naturally occurring compounds, especially those from dietary sources, are receiving increasing consideration for prevention and treatment of diseases including cancer. There is a growing need for innovative anticancer therapies and therefore search for natural compounds with novel biological activities or antineoplastic potential is currently an important area in drug discovery. Support for this interest also comes from increasing concern over the efficacy and safety of many conventional therapies, especially those that run over a long course of time. Laboratory studies in different in vitro and in vivo systems have shown that many natural compounds possess the capacity to regulate response to oxidative stress and DNA damage, suppress angiogenesis, inhibit cell proliferation and induce autophagy and apoptosis. This review discusses the induction of apoptosis and autophagy as a mechanism of cancer prevention by some of the most studied naturally occurring dietary compounds.
Apoptosis; Autophagy; Chemoprevention; Cancer; Dietary; Agents
Lysophosphatidic acids are structurally simple lipid phosphate esters with a now widely appreciated role as extracellular signaling molecules. LPA binds to selective cell surface receptors to promote cell growth, survival, motility and differentiation. Studies using LPA receptor knockout mice and experimental therapeutics targeting these receptors identify roles for LPA signaling in processes that include cardiovascular disease and function, angiogenesis, reproduction, cancer progression and neuropathic pain. These studies identify considerable functional redundancy between these receptors and raise the possibility that additional lysophosphatidic acid receptors remain to be identified. Lysophosphatidic acid is present in the blood and other biological fluids at physiologically relevant concentrations and can likely be rapidly generated and degraded in different locations, for example at sites of inflammation, vascular injury and thrombosis or in the tumor micro environment. Recent work identifies a secreted enzyme, autotaxin, as the key component of an extracellular pathway for generation of lysophosphatidic acid by lysophospholipase D catalyzed hydrolysis of lysophospholipid substrates. In contrast to the apparently redundant functions of LPA receptors, studies using autotaxin knock out and transgenic mice indicate that this enzyme is uniquely required for LPA signaling during early development and serves as the primary determinant of circulating LPA levels in adult animals. Accordingly, pharmacological inhibition of autotaxin may be a viable and potentially effective way to interfere with LPA signaling in the cardiovascular system and possibly other settings such as tumor metastasis for therapeutic benefit. In this review we provide an update on recent advances in defining roles for LPA signaling in major disease processes and discuss recent progress in understanding the regulation and function of autotaxin focusing on strategies for the identification and initial evaluation of small molecule autotaxin inhibitors.
Lysophosphatidic acid; phospholipase; receptor; autotaxin; cancer; cardiovascular disease; molecular therapeutics
The first barrier that an antimicrobial agent must overcome when interacting with its target is the microbial cell wall. In the case of Gram-negative bacteria, additional to the cytoplasmic membrane and the peptidoglycan layer, an outer membrane (OM) is the outermost barrier. The OM has an asymmetric distribution of the lipids with phospholipids and lipopolysaccharide (LPS) located in the inner and outer leaflets, respectively. In contrast, Gram-positive bacteria lack OM and possess a much thicker peptidoglycan layer compared to their Gram-negative counterparts. An additional class of amphiphiles exist in Gram-positives, the lipoteichoic acids (LTA), which may represent important structural components. These long molecules cross-bridge the entire cell envelope with their lipid component inserting into the outer leaflet of the cytoplasmic membrane and the teichoic acid portion penetrating into the peptidoglycan layer. Furthermore, both classes of bacteria have other important amphiphiles, such as lipoproteins, whose importance has become evident only recently.
It is not known yet whether any of these amphiphilic components are able to stimulate the immune system under physiological conditions as constituents of intact bacteria. However, all of them have a very high pro-inflammatory activity when released from the cell. Such a release may take place through the interaction with the immune system, or with antibiotics (particularly with those targeting cell wall components), or simply by the bacterial division. Therefore, a given antimicrobial agent must ideally have a double character, namely, it must overcome the bacterial cell wall barrier, without inducing the liberation of the pro-inflammatory amphiphiles. Here, new data are presented which describe the development and use of membrane-active antimicrobial agents, in particular antimicrobial peptides (AMPs) and lipopolyamines. In this way, essential progress was achieved, in particular with respect to the inhibition of deleterious consequences of bacterial infections such as severe sepsis and septic shock.
Antimicrobial peptides; endotoxin shock; lipopolyamines; lipopolysaccharides; tumor-necrosis-factorα
Despite advances in therapy for many of the most common cancers, advances which have led to corresponding improvements in survival rates, progress on the pancreatic cancer front have been slow and mortality rates remain startlingly high. New therapeutic strategies are needed. Phytochemicals are naturally occurring, plant-based substances that have garnered much interest in the research world for their anti-cancer properties, both as therapeutics and as components of the diet for chemoprevention. One particularly ubiquitous group of phytochemicals is the polyphenolic flavonoids. Baicalein, one such flavonoid, which has been widely studied in several malignancies, shows potent activity against pancreatic adenocarcinoma in both in vitro and in vivo studies. The mechanisms by which baicalein accomplishes this have recently been elucidated, and is through an induction of apoptosis in pancreatic cancer cells that are fiercely resistant to cell death. Compounds such as baicalein, offer promise in dietary chemoprevention, as chemotherapeutic adjuvants, or as targeted therapy.
Apoptosis; baicalein; bioavailability; pancreatic cancer; phytochemical; prevention; treatment
Preeclampsia is an important syndrome complicating pregnancy. While the pathogenesis of preeclampsia is not entirely known, poor placental perfusion leading to widespread maternal endothelial dysfunction is accepted as a major mechanism. It has been suggested that altered placental expression of matrix metalloproteinases (MMPs) may cause shallow cytotrophoblastic invasion and incomplete remodeling of the spiral arteries. MMPs are also thought to link placental ischemia to the cardiovascular alterations of preeclampsia. In fact, MMPs may promote vasoconstriction and surface receptors cleavage affecting the vasculature. Therefore, the overall goal of this review article is to provide an overview of the pathophisiology of preeclampsia, more specifically regarding the role of MMPs in the pathogenesis of preeclampsia and the potential of MMP inhibitors as therapeutic options.
Hypertension; hypertensive disorders; matrix metalloproteinases; preeclampsia; pregnancy; therapy
Plasminogen Activator Inhibitor-1 (PAI-1) is a multifunctional protein with the ability to not only regulate fibrinolysis through inhibition of plasminogen activation, but also cell signaling events which have direct downstream effects on cell function. Elevated plasma levels of this protein have been shown to have profound effects on the development and progression of cardiovascular diseases. However, results from a number of studies, especially those using PAI-1 deficient mouse models, have demonstrated that its function is ambiguous, with evidence of both preventing and enhancing various disease states. A number of lifestyle changes and pharmacological reagents have been identified that can regulate PAI-1 levels or function. Those reagents that target function are focused on its ability to regulate plasmin formation, and have been studied in vivo models of thrombosis. Further investigations involving regulation of cell function could potentially resolve paradoxical issues associated with the function of this protein in regulating cardiovascular disease.
plasminogen activator inhibitor-1; gene knock out mice; cardiovascular disease
Atherosclerosis is a self-sustaining inflammatory fibroproliferative disease that progresses in discrete stages and involves a number of cell types and effector molecules. The potential importance of the coagulation, anticoagulation, and fibrinolytic systems in atherosclerosis is based on the observation that fibrin deposits and fibrin degradation products are resident in atherosclerotic plaques. A number of investigations have been conducted to probe the relationships between components of the hemostasis system and atherosclerosis; and these types of studies proliferated after the availability of mice genetically manipulated to emphasize the impact of genes of interest. In order to summarize recent progress in this area, this review is focused on mice lacking individual hemostasis genes and their contributions to steps of the atherosclerotic process.
The ability of the innate immune system to quickly recognize and respond to an invading pathogen is essential for controlling the infection. For this purpose, cells of the immune system express receptors which recognize evolutionarily conserved structures expressed by various pathogens but absent from host cells. In this review we focus on the non-classical C-type lectin receptors including Dectin-1 whose role has been extensively characterized in the recognition and response to fungal pathogens. Dectin-1 is a type II transmembrane protein which binds β-1,3 and β-1,6 glucans. It is expressed on most cells of the innate immune system and has been implicated in phagocytosis as well as killing of fungi by macrophages, neutrophils and dendritic cells. The Dectin-1 cytoplasmic tail contains an immunoreceptor tyrosine based activation motif (ITAM) that signals in part through the spleen tyrosine kinase and in collaboration with Toll-like receptors. Although the main research focus has been on Dectin-1’s role as a fungal and yeast pathogen recognition receptor, more recent studies suggest that Dectin-1 may have a broader function in pathogen recognition including a role in directing a macrophage response to mycobacterial infections.
Pattern recognition receptors; Dectin-1; signaling; mycobacteria; fungi; glucans; C-type lectin
New blood vessel formation (angiogenesis) is fundamental to tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) signaling pathway plays pivotal roles in regulating tumor angiogenesis. VEGF as a therapeutic target has been validated in various types of human cancers. Different agents including antibodies, aptamers, peptides, and small molecules have been extensively investigated to block VEGF and its pro-angiogenic functions. Some of these agents have been approved by FDA and some are currently in clinical trials. Combination therapies are also being pursued for better tumor control. By providing comprehensive real-time information, molecular imaging of VEGF pathway may accelerate the drug development process. Moreover, the imaging will be of great help for patient stratification and therapeutic effect monitoring, which will promote effective personalized molecular cancer therapy. This review summarizes the current status of tumor therapeutic agents targeting to VEGF and the applications of VEGF related molecular imaging.
Vascular endothelial growth factor; VEGF; targeted therapy; molecular imaging
The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor.
In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction.
The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.
Opioids; opioid receptors; neurotransmitters; function; brain; heart; lung; ionic homeostasis; neuroprotection; hibernation; pain; hypoxia; ischemia
Protons are important signals for neuronal function. In the central nervous system (CNS), proton concentrations change locally when synaptic vesicles release their acidic contents into the synaptic cleft, and globally in ischemia, seizures, traumatic brain injury, and other neurological disorders due to lactic acid accumulation. The finding that protons gate a distinct family of ion channels, the acid-sensing ion channels (ASICs), has shed new light on the mechanism of acid signaling and acidosis-associated neuronal injury. Accumulating evidence has suggested that ASICs play important roles in physiological processes such as synaptic plasticity, learning/memory, fear conditioning, and retinal integrity, and in pathological conditions such as brain ischemia, multiple sclerosis, epileptic seizures, and malignant glioma. Thus, targeting these channels may lead to novel therapeutic interventions for neurological disorders. The goal of this review is to provide an update on recent advances in our understanding of the functions of ASICs in the CNS.
Acid-sensing ion channel; acidosis; CNS; neuron; function; neurological disease
The hypothesis that tumors may originate from a rare population of cancer stem cells (CSCs) has gained tremendous popularity in recent years and is supported extensively by several pioneering works. Cancer therapies targeting CSCs have unlimited potential for relapse free survival of cancer patients. As a result, knowledge of biological pathways that govern CSCs is very important and this review is focused on the biology of CSCs and recent advances in therapeutic approaches targeting them.
Breast cancer; cancer stem cell; cancer therapy; drug resistance; signaling pathway; stem cell
Loss of heterozygosity (LOH) at human chromosome 18q, which includes the gene Deleted in Colorectal Cancer (DCC), has been linked to colorectal and many other human cancers. DCC encodes the receptor for the axon guidance molecule Netrin (Net) and functions during neural development in a variety of organisms. However, since its discovery in the 1990s, the status of DCC as a tumor suppressor has been debated, primarily due to a lack of support for this hypothesis in animal models. A recent study from our laboratory capitalized on the genetic tractability of Drosophila melanogaster to demonstrate that this gene functions as an invasive tumor suppressor, thereby providing the first direct link between DCC loss and metastatic phenotypes in an animal model for cancer. Two subsequent studies from other laboratories have demonstrated that DCC suppresses tumor progression and metastasis in murine colorectal and mammary tumor models. Combined, these findings have prompted the rebirth of DCC as a tumor suppressor and highlighted the need for continued analysis of DCC function in animal models for human cancer.
Apoptosis; axon guidance; cancer; DCC; Drosophila melanogaster; metastasis; netrin; tumor suppressor
Cyanobacteria are considered a promising source for new pharmaceutical lead compounds and a large number of chemically diverse and bioactive metabolites have been obtained from cyanobacteria over the last few decades. This review highlights the structural diversity of natural products from freshwater and terrestrial cyanobacteria. The review is divided into three areas: cytotoxic metabolites, protease inhibitors, and antimicrobial metabolites. The first section discusses the potent cytotoxins cryptophycin and tolytoxin. The second section covers protease inhibitors from freshwater and terrestrial cyanobacteria and is divided in five subsections according to structural class: aeruginosins, cyanopeptolins, microviridins, anabaenopeptins, and microginins. Structure activity relationships are discussed within each protease inhibitor class. The third section, antimicrobial metabolites from freshwater and terrestrial cyanobacteria, is divided by chemical class in three subsections: alkaloids, peptides and terpenoids. These examples emphasize the structural diversity and drug development potential of natural products from freshwater and terrestrial cyanobacteria.
cyanobacteria; cytotoxic; protease inhibitor; antibacterial; antifungal
The diacylglycerol-responsive C1 domains of protein kinase C and of the related classes of signaling proteins represent highly attractive targets for drug development. The signaling functions that are regulated by C1 domains are central to cellular control, thereby impacting many pathological conditions. Our understanding of the diacylglycerol signaling pathways provides great confidence in the utility of intervention in these pathways for treatment of cancer and other conditions. Multiple compounds directed at these signaling proteins, including compounds directed at the C1 domains, are currently in clinical trials, providing strong validation for these targets. Extensive understanding of the structure and function of C1 domains, coupled with detailed insights into the molecular details of ligand –C1 domain interactions, provides a solid basis for rational and semi-rational drug design. Finally, the complexity of the factors contributing to ligand – C1 domain interactions affords abundant opportunities for manipulation of selectivity; indeed, substantially selective compounds have already been identified.
protein kinase C; phorbol ester; RasGRP; bryostatin; C1 domain
Increasingly recognized as bioactive molecules, sphingolipids have been studied in a variety of disease models. The impact of sphingolipids on cancer research facilitated the entry of sphingolipid analogues and enzyme modulators into clinical trials. Owing to its ability to regulate two bioactive sphingolipids, ceramide and sphingosine-1-phosphate, acid ceramidase (AC) emerges as an attractive target for drug development within the sphingolipid metabolic pathway. Indeed, there is extensive evidence supporting a pivotal role for AC in lipid metabolism and cancer biology. In this article, we review the current knowledge of the biochemical properties of AC, its relevance to tumor promotion, and its molecular targeting approaches.
Ceramidase; sphingolipids; ceramide; sphingosine; cancer therapy