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The cardiovascular unit as a dynamic player in disease and regeneration.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cell-mediated cardiac regeneration remains a challenge as a therapeutic option in heart failure, but modest success using experimental models suggests that a better understanding of normal histogenesis will be needed to make progress towards cardiac regeneration. Recent studies of the heart show that the interstitium informs organogenesis and responsiveness to pathological stimuli through continuous bidirectional cross-talk between cardiomyocytes and non-cardiac cells. Here, we introduce the concept of the "cardiovascular unit" (CVU) as a building block of the heart, which includes cardiomyocytes and adjacent capillari...
Source: Trends in Molecular Medicine - November 11, 2009 Category: Molecular Biology Authors: Ausoni S, Sartore S Tags: Trends Mol Med Source Type: journals

Dual oxidases and hydrogen peroxide in a complex dialogue between host mucosae and bacteria.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Among the host defense mechanisms against bacteria, leukocyte phagocytosis leads to their hydrogen peroxide (H(2)O(2))-mediated destruction. The recent discovery of dual oxidase (DUOX)-dependent H(2)O(2) generation associated with peroxidase and thiocyanate secretion at the apex of mucosal cells has been similarly interpreted as a killing mechanism. However, the rapid degradation of H(2)O(2) would be expected to reduce the efficiency of this system. It has been demonstrated that H(2)O(2) acts as a chemorepellent for bacteria, and such an effect might be sufficient to block cellular infection. Therefore, H(2)O(2) genera...
Source: Trends in Molecular Medicine - November 11, 2009 Category: Molecular Biology Authors: Allaoui A, Botteaux A, Dumont JE, Hoste C, De Deken X Tags: Trends Mol Med Source Type: journals

RNA-targeting approaches for neuromuscular diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although most molecular therapy strategies for genetic diseases are based on gene replacement, interesting alternative approaches target RNA. These strategies rely on the modification of the mutated gene's expression in vivo by modulating pre-mRNA splicing, mRNA stability or mRNA translation. Here, we review recent progress using these RNA-based approaches in the field of muscle and muscle-related genetic diseases. Different molecular tools, including modified antisense oligonucleotides, pre-mRNA trans-splicing molecules, ribozymes or chemical compounds have been used successfully on patient cells or animal models of d...
Source: Trends in Molecular Medicine - November 9, 2009 Category: Molecular Biology Authors: Le Roy F, Charton K, Lorson CL, Richard I Tags: Trends Mol Med Source Type: journals

One-carbon metabolism and schizophrenia: current challenges and future directions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Schizophrenia is a heterogeneous disease generally considered to result from a combination of heritable and environmental factors. Although its pathophysiology has not been fully determined, biological studies support the involvement of several possible components including altered DNA methylation, abnormal glutamatergic transmission, altered mitochondrial function, folate deficiency and high maternal homocysteine levels. Although these factors have been explored separately, they all involve one-carbon (C1) metabolism. Furthermore, C1 metabolism is well positioned to integrate gene-environment interactions by influenci...
Source: Trends in Molecular Medicine - November 5, 2009 Category: Molecular Biology Authors: Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H Tags: Trends Mol Med Source Type: journals

Pseudoviral immunity - a novel concept for lupus.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Systemic lupus erythematosus (SLE or lupus) is a polygenic syndrome of immunity against nuclear autoantigens. Recent data from several fields now suggest 'pseudoviral' immunity as a novel disease concept. Known lupus risk factors commonly compromise those mechanisms that protect chromatin and ribonucleoprotein particles from activating viral nucleic acid sensors. This process activates antigen-presenting cells and induces type I interferons. These central mediators of antiviral immunity have similar proinflammatory roles in lupus, explaining overlapping clinical manifestations, immunopathology and ultrastructural abnor...
Source: Trends in Molecular Medicine - November 4, 2009 Category: Molecular Biology Authors: Anders HJ Tags: Trends Mol Med Source Type: journals

Brain cancer propagating cells: biology, genetics and targeted therapies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cancer propagating cells (CPCs) within primary central nervous system (CNS) tumors (glioblastoma multiforme (GBM), medulloblastoma (MB) and ependymoma) might be integral to tumor development and perpetuation. These cells, also known as brain cancer propagating cells (BCPCs), have the ability to self-renew and proliferate. BCPCs can initiate new tumors in mice with high efficiency and these exhibit many features that are characteristic of patient's brain tumors. Accumulating evidence suggests that BCPCs might originate from the transformation of neural stem cells (NSCs) and their progenitors. Furthermore, recent studies...
Source: Trends in Molecular Medicine - November 2, 2009 Category: Molecular Biology Authors: Hadjipanayis CG, Van Meir EG Tags: Trends Mol Med Source Type: journals

Strategies for targeted nonviral delivery of siRNAs in vivo.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Silencing specific gene expression by RNA interference (RNAi) has rapidly become a standard tool for the reverse genetic analysis of gene functions. It also has tremendous potential for managing diseases for which effective treatment is currently unavailable or suboptimal. However, the poor cellular uptake of synthetic small interfering RNAs (siRNAs) is a major impediment for their clinical use. Great progress has been made in recent years to overcome this barrier, and several methods have been described for the in vivo delivery of siRNA. Moreover, the latest advances have focused on achieving targeted siRNA delivery r...
Source: Trends in Molecular Medicine - October 18, 2009 Category: Molecular Biology Authors: Kim SS, Garg H, Joshi A, Manjunath N Tags: Trends Mol Med Source Type: journals

Fetal-maternal exchange of multipotent stem/progenitor cells: microchimerism in diagnosis and disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The biological concept of microchimerism, the bidirectional trafficking and stable long-term persistence of small numbers of allogeneic (fetal and maternal) cells in a genetically different organ, has gained considerable attention. Microchimerism is a common phenomenon in many species, including humans, and microchimeric cells can modify immunological recognition or tolerance, affect the course and outcome of various diseases and demonstrate stem cell-like or regenerative potential. Here, we review current knowledge of the biology of microchimerism and show how long-term allogeneic co-existence within an organism can i...
Source: Trends in Molecular Medicine - October 11, 2009 Category: Molecular Biology Authors: Klonisch T, Drouin R Tags: Trends Mol Med Source Type: journals

Emerging biology of vascular wall progenitor cells in health and disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
New blood vessels are formed through angiogenesis and postnatal vasculogenesis. Thus, it is essential to identify vascular stem and progenitor cell niches and the mechanisms governing their role in blood vessel formation. Although much is known about circulating and bone marrow-derived endothelial progenitor cells (EPCs), little is known about the vascular wall as an EPC niche. Experimental evidence strongly suggests that EPCs, as well as other stem and progenitor cells, reside in distinct zones of the vessel wall, such as within the subendothelial space and in the so-called "vasculogenic zone" within the vascular adve...
Source: Trends in Molecular Medicine - October 11, 2009 Category: Molecular Biology Authors: Tilki D, Hohn HP, Ergün B, Rafii S, Ergün S Tags: Trends Mol Med Source Type: journals

p53 and the regulation of hepatocyte apoptosis: implications for disease pathogenesis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The interplay between p53 and apoptosis in diseases such as cancer, neurodegeneration, ischemia and atherosclerosis underscores the need to understand the complexity of p53 networks. Here, we highlight recent studies of p53-induced apoptosis in human diseases, with a focus on the modulation of liver cell apoptosis. In addition, recent work has provided new insights into mechanisms underlying the antiapoptotic functions of the endogenous bile acid ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm2 is a key step in the UDCA modulation of deregulated, p53-triggered apoptosis. The...
Source: Trends in Molecular Medicine - October 9, 2009 Category: Molecular Biology Authors: Amaral JD, Castro RE, Steer CJ, Rodrigues CM Tags: Trends Mol Med Source Type: journals

Irritable bowel syndrome: towards biomarker identification.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder referred to gastroenterologists, affects 7-10% of the general population worldwide. The lack of suitable disease-defining biological markers coupled with a poorly understood underlying pathophysiology complicates patient diagnosis and seriously hampers drug discovery efforts. Over the past few years, a number of potential biomarkers have emerged, and in this review we critically evaluate such candidates. In particular, we highlight the increasing number of studies supporting a low-grade immune activation in IBS and consider how the lat...
Source: Trends in Molecular Medicine - October 4, 2009 Category: Molecular Biology Authors: Clarke G, Quigley EM, Cryan JF, Dinan TG Tags: Trends Mol Med Source Type: journals

Oxidative stress in bone remodelling and disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Oxidative stress is characterised by an increased level of reactive oxygen species (ROS) that disrupts the intracellular reduction-oxidation (redox) balance. Although initially shown to be involved in aging, physiological roles for ROS in regulating cell functions and mediating intracellular signals have emerged. In bone tissues, recent studies have demonstrated that ROS generation is a key modulator of bone cell function and that oxidative status influences the pathophysiology of mineralised tissues. Here, we review the crucial role of oxidative stress in bone pathophysiology, and discuss the possibility that ROS prod...
Source: Trends in Molecular Medicine - October 4, 2009 Category: Molecular Biology Authors: Wauquier F, Leotoing L, Coxam V, Guicheux J, Wittrant Y Tags: Trends Mol Med Source Type: journals

The neurovascular link in health and disease: an update.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Although the nervous and vascular systems are functionally different, they show a high degree of anatomic parallelism and cross-talk. They also share similar mechanisms and molecular cues that regulate their development and maintenance. Malfunctioning of this cross-talk can cause or influence several vascular and neuronal disorders. In this review, we first provide a brief overview of the molecular and cellular mechanisms that govern the neurovascular link. Second, we focus on two neurodegenerative diseases, Alzheimer's disease and amyotrophic lateral sclerosis, to illustrate how a defective neurovascular link might co...
Source: Trends in Molecular Medicine - October 1, 2009 Category: Molecular Biology Authors: Segura I, De Smet F, Hohensinner PJ, Almodovar CR, Carmeliet P Tags: Trends Mol Med Source Type: journals

Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Pigment epithelium-derived factor (PEDF) has roles in antiangiogenesis and antitumourigenesis that are intimately entwined and is showing promise as a potential anticancer agent. However, the function of PEDF in the deregulated apoptotic pathways of malignant cells must first be fully characterized. Here, we review the currently known apoptotic pathways that are relevant to PEDF and cancer. Recently, a pathway that includes the PEDF receptor, PPARgamma and p53 has emerged. It is hoped that further characterization of this and other pathways involved in cancer will bring to light potential new therapeutic targets and ap...
Source: Trends in Molecular Medicine - September 24, 2009 Category: Molecular Biology Authors: Broadhead ML, Dass CR, Choong PF Tags: Trends Mol Med Source Type: journals

Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The protected transport of nitric oxide (NO) by hemoglobin (Hb) links the metabolic activity of working tissue to the regulation of its local blood supply through hypoxic vasodilation. This physiologic mechanism is allosterically coupled to the O(2) saturation of Hb and involves the covalent binding of NO to a cysteine residue in the beta-chain of Hb (Cys beta93) to form S-nitrosohemoglobin (SNO-Hb). Subsequent S-transnitrosation, the transfer of NO groups to thiols on the RBC membrane and then in the plasma, preserves NO vasodilator activity for delivery to the vascular endothelium. This SNO-Hb paradigm provides insig...
Source: Trends in Molecular Medicine - September 22, 2009 Category: Molecular Biology Authors: Allen BW, Stamler JS, Piantadosi CA Tags: Trends Mol Med Source Type: journals

Mechanisms of bone repair and regeneration.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Bone problems can have a highly deleterious impact on life and society, therefore understanding the mechanisms of bone repair is important. In vivo studies show that bone repair processes in adults resemble normal development of the skeleton during embryogenesis, which can thus be used as a model. In addition, recent studies of skeletal stem cell biology have underlined several crucial molecular and cellular processes in bone formation. Hedgehog, parathyroid hormone-related protein, Wnt, bone morphogenetic proteins and mitogen-activated protein kinases are the main molecular players, and osteoclasts and mesenchymal ste...
Source: Trends in Molecular Medicine - September 6, 2009 Category: Molecular Biology Authors: Deschaseaux F, Sensébé L, Heymann D Tags: Trends Mol Med Source Type: journals

Vascular calcification and bone disease: the calcification paradox.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Vascular calcification or ectopic mineralization in blood vessels is an active, cell-regulated process, increasingly recognized as a general cardiovascular risk factor. Remarkably, ectopic artery mineralization is frequently accompanied by decreased bone mineral density or disturbed bone turnover. This contradictory association, observed mainly in osteoporosis and chronic kidney disease, is called the 'calcification paradox'. Here, we review recent advances in our understanding of the calcification paradox, including protein expression patterns governing both normal and ectopic mineralization, the conversion of vascula...
Source: Trends in Molecular Medicine - September 1, 2009 Category: Molecular Biology Authors: Persy V, D'Haese P Tags: Trends Mol Med Source Type: journals

Protein S-nitrosylation in health and disease: a current perspective.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates important roles for S-nitrosylation both in normal physiology and in a broad spectrum of human diseases. Here we review recent findings that implicate S-nitrosylation in cardiovascular, pulmonary, musculoskeletal and neurological (dys)function, as well as in cancer. The emerging picture shows that, in many cases, pathophysiology correlates with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to loss of or enh...
Source: Trends in Molecular Medicine - August 30, 2009 Category: Molecular Biology Authors: Foster MW, Hess DT, Stamler JS Tags: Trends Mol Med Source Type: journals

Making sense of nonsense GABA(A) receptor mutations associated with genetic epilepsies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nonsense mutations that generate premature translation-termination codons (PTCs) are responsible for approximately one- third of human genetic diseases. PTCs in both voltage- and ligand-gated ion channel genes, including those for sodium, potassium, nicotinic cholinergic receptor and GABA(A) receptor channels, have been associated with genetic epilepsies but the epilepsy syndromes they cause are variable. It was recently proposed that two well-established molecular pathways, nonsense-mediated decay (NMD) and endoplasmic reticulum-associated degradation (ERAD), determine the effects of PTCs in GABA(A) receptor subunit g...
Source: Trends in Molecular Medicine - August 27, 2009 Category: Molecular Biology Authors: Kang JQ, Macdonald RL Tags: Trends Mol Med Source Type: journals

Towards the definition of prostate cancer-related microRNAs: where are we now?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Eradication of advanced prostate cancer still represents an unsolved clinical problem, making the development of alternative treatment approaches highly desirable. Understanding the molecular alterations that distinguish non-progressive from progressive disease would provide mechanistic information for the identification of new therapeutic targets. Recent findings indicate that human tumors have deregulated expression of microRNAs, which have thus been proposed as novel oncogenes or tumor suppressors. A few studies have analyzed the expression profiles or the functional role of microRNAs in prostate cancer, generating ...
Source: Trends in Molecular Medicine - August 26, 2009 Category: Molecular Biology Authors: Gandellini P, Folini M, Zaffaroni N Tags: Trends Mol Med Source Type: journals

The role of bone-marrow-derived cells in tumor growth, metastasis initiation and progression.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Emerging evidence from murine models suggests that tumor-specific endocrine factors systemically stimulate the quiescent bone marrow (BM) compartment, resulting in the expansion, mobilization and recruitment of BM progenitor cells. Discrete subsets of tumor-instigated BM-derived progenitor cells support tumor progression and metastasis by regulating angiogenesis, inflammation and immune suppression. Notably, clinical studies have begun to reveal that increased BM recruitment in tumors is associated with poor prognosis. Thus, the BM-derived tumor microenvironment is an attractive therapeutic target, and drugs targeting ...
Source: Trends in Molecular Medicine - August 6, 2009 Category: Molecular Biology Authors: Gao D, Mittal V Tags: Trends Mol Med Source Type: journals

Cytoplasmic nucleic acid sensors in antiviral immunity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The innate immune system uses pattern recognition receptors (PRRs) to sense invading microbes and initiate a rapid protective response. PRRs bind and are activated by structural motifs, such as nucleic acids or bacterial and fungal cell wall components, collectively known as pathogen-associated molecular patterns. PRRs that recognize pathogen-derived nucleic acids are present in vesicular compartments and in the cytosol of most cell types. Here, we review recent studies of these cytosolic sensors, focusing on the nature of the ligands for DNA-dependent activator of interferon (DAI)-regulatory factors, absent in melanom...
Source: Trends in Molecular Medicine - August 5, 2009 Category: Molecular Biology Authors: Ranjan P, Bowzard JB, Schwerzmann JW, Jeisy-Scott V, Fujita T, Sambhara S Tags: Trends Mol Med Source Type: journals

p38(MAPK): stress responses from molecular mechanisms to therapeutics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discus...
Source: Trends in Molecular Medicine - August 5, 2009 Category: Molecular Biology Authors: Coulthard LR, White DE, Jones DL, McDermott MF, Burchill SA Tags: Trends Mol Med Source Type: journals

Gene therapy and bone marrow stem-cell transfer to treat autoimmune disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Current treatment of human autoimmune disease by autologous bone marrow stem-cell transfer is hampered by frequent disease relapses. This is most probably owing to re-emergent self-reactive lymphocytes. Gene therapy combined with bone marrow stem cells has successfully introduced genes lacking in immunodeficiences. Because the bone marrow compartment has a key role in establishing immune tolerance, this combination strategy should offer a rational approach to prevent re-emergent self-reactive lymphocytes by establishing solid, life-long immune tolerance to causative self-antigen. Indeed, we have recently demonstrated t...
Source: Trends in Molecular Medicine - August 5, 2009 Category: Molecular Biology Authors: Alderuccio F, Chan J, Scott DW, Toh BH Tags: Trends Mol Med Source Type: journals

Protein-binding microarrays: probing disease markers at the interface of proteomics and genomics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
DNA-binding proteins mediate a variety of crucial molecular functions, such as transcriptional regulation and chromosome maintenance, replication and repair, which in turn control cell division and differentiation. The roles of these proteins in disease are currently being investigated using microarray-based approaches. However, these assays can be difficult to adapt to routine diagnosis of complex diseases such as cancer. Here, we review promising alternative approaches involving protein-binding microarrays (PBMs) that probe the interaction of proteins from crude cell or tissue extracts with large collections of synth...
Source: Trends in Molecular Medicine - August 5, 2009 Category: Molecular Biology Authors: Kerschgens J, Egener-Kuhn T, Mermod N Tags: Trends Mol Med Source Type: journals

Molecular therapies for heritable blistering diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tremendous progress has been made over the past two decades in understanding the molecular genetics of heritable skin diseases. The paradigm for such conditions is epidermolysis bullosa (EB), which comprises a group of heritable blistering disorders caused by mutations in ten genes expressed in the cutaneous basement membrane zone and has high morbidity and mortality. Identification of distinct mutations has improved the diagnosis and subclassification of EB, leading to improvements in disease prognosis, and has provided a basis for prenatal and pre-implantation genetic diagnosis for this disorder. Nevertheless, there ...
Source: Trends in Molecular Medicine - July 3, 2009 Category: Molecular Biology Authors: Tamai K, Kaneda Y, Uitto J Tags: Trends Mol Med Source Type: journals

Type II transmembrane serine proteases in cancer and viral infections.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Regulated proteolysis of cellular factors is pivotal to tissue development and homeostasis, whereas uncontrolled proteolytic activity is linked to disease. Type II transmembrane serine proteases (TTSPs) are expressed at the cell surface and are thus ideally located to regulate cell-cell and cell-matrix interactions. Increasing evidence demonstrates that aberrant expression of TTSPs is a hallmark of several cancers and recent studies have defined molecular mechanisms underlying TTSP-promoted carcinogenesis. In addition, new findings suggest that influenza and other respiratory viruses could exploit TTSPs to promote thei...
Source: Trends in Molecular Medicine - July 3, 2009 Category: Molecular Biology Authors: Choi SY, Bertram S, Glowacka I, Park YW, Pöhlmann S Tags: Trends Mol Med Source Type: journals

Biomarkers of premature atherosclerosis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
C-reactive protein (CRP) is an acute phase protein and a biochemical marker with important prognostic value for cardiovascular events. Interleukins IL-1 and IL-6 are implicated in the pathogenesis of atherosclerosis and are associated with CRP. Apolipoproteins ApoA-I and ApoB are the main lipid metabolic markers implicated in the development and progression of atherosclerosis. Fibrinogen has also been proposed to be a major independent risk factor for cardiovascular events. Because premature atherosclerosis precedes the development of cardiovascular disease, identification of the associated biomarkers is of great impor...
Source: Trends in Molecular Medicine - July 2, 2009 Category: Molecular Biology Authors: Kampoli AM, Tousoulis D, Antoniades C, Siasos G, Stefanadis C Tags: Trends Mol Med Source Type: journals

Cdx genes, inflammation and the pathogenesis of Barrett's metaplasia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Metaplasia is the conversion of one cell or tissue type to another and can predispose patients to neoplasia. Perhaps one of the best-known examples of metaplasia is Barrett's metaplasia (BM), a pathological condition in which the distal oesophageal epithelium switches from stratified squamous to intestinal-type columnar epithelium. BM predisposes to oesophageal adenocarcinoma and is the consequence of long-term acid bile reflux. The incidence of BM and oesophageal adenocarcinoma has risen dramatically in recent years. A key event in the pathogenesis of BM is the induction of oesophageal CDX2 expression. Importantly, re...
Source: Trends in Molecular Medicine - June 26, 2009 Category: Molecular Biology Authors: Colleypriest BJ, Palmer RM, Ward SG, Tosh D Tags: Trends Mol Med Source Type: journals

Organelle interplay in peroxisomal disorders.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Peroxisomes are no longer regarded as autonomous organelles because evidence for their interplay with other cellular organelles is emerging. Peroxisomes interact with mitochondria in several metabolic pathways, including beta-oxidation of fatty acids and the metabolism of reactive oxygen species. Both organelles are in close contact with the endoplasmic reticulum (ER) and share several proteins, including organelle fission factors. Today, the study of peroxisome biogenesis disorders mainly focuses on metabolic defects such as accumulation of very long chain fatty acids or plasmalogen deficiency. In addition to metaboli...
Source: Trends in Molecular Medicine - June 25, 2009 Category: Molecular Biology Authors: Thoms S, Grønborg S, Gärtner J Tags: Trends Mol Med Source Type: journals

Strategies for recruiting and targeting dendritic cells for optimizing HIV vaccines.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The natural immune response against HIV and other pathogens that cause chronic infection is insufficient for protection. Novel vaccine design and delivery strategies for optimization of HIV vaccines are urgently needed. These will require a better understanding of a number of factors including: the interplay between dendritic cells (DCs) and multiple cell types in linking innate signals that orchestrate subsequent adaptive immune responses; the regulation of DC function by viral and bacterial vectors, adjuvants and immunomodulatory molecules; and the temporal and synergistic relationships between C-type lectins, Toll-l...
Source: Trends in Molecular Medicine - May 30, 2009 Category: Molecular Biology Authors: Ahlers JD, Belyakov IM Tags: Trends Mol Med Source Type: journals

Natural killer and gammadelta T cells in haematological malignancies: enhancing the immune effectors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Human natural killer (NK) and gamma delta (gammadelta) T cells are potent effectors involved in the destruction of abnormal cells. Accumulating clinical and experimental data point towards a key role for NK cells and gammadelta T cells in the control of most, if not all, haematological malignancies. This review focuses on the alterations in these effector cells found in patients with haematological malignancies, which might explain an escape from innate immune surveillance. We discuss new anti-cancer drugs that target these effector cells indirectly or directly. Finally, we review future strategies that offer the possi...
Source: Trends in Molecular Medicine - May 30, 2009 Category: Molecular Biology Authors: Rey J, Veuillen C, Vey N, Bouabdallah R, Olive D Tags: Trends Mol Med Source Type: journals

Non-invasive molecular imaging of prostate cancer lymph node metastasis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe the new techniques and compare their accuracy in detecting LN metastasis in prostate cancer. We also present new molecular strategies for improving tumor detection using adenoviruses, molecular promoters and amplification systems. Finally, we present the concept of 'in vivo pathology', which envisages using molecular imaging to accurately localize metastatic lesions based on the molecular signature of the disease. PMID: 19482514 [PubMed - as supplied by publisher] (Source: Trends in Molecular Medicine)
Source: Trends in Molecular Medicine - May 29, 2009 Category: Molecular Biology Authors: Pouliot F, Johnson M, Wu L Tags: Trends Mol Med Source Type: journals

Epithelial metaplasia: adult stem cell reprogramming and (pre)neoplastic transformation mediated by inflammation?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Throughout adult life, new developmental commitment of adult stem cells causes metaplastic conversions to occur frequently in some organs. These reversible epithelial replacements are almost always observed in association with chronic inflammation and persistent irritation. Although metaplasia is not synonymous with dysplasia, clinical surveillance has demonstrated that these adaptive processes have an increased susceptibility to evolve into cancer. We propose that cytokines and other soluble factors released by both epithelial and inflammatory cells might alter the transcription-factor expression profile of stem cells...
Source: Trends in Molecular Medicine - May 18, 2009 Category: Molecular Biology Authors: Herfs M, Hubert P, Delvenne P Tags: Trends Mol Med Source Type: journals

Multiple sclerosis - a response-to-damage model.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
According to a widely supported but unproven concept, the autoimmune mechanisms that drive neuroinflammation in multiple sclerosis (MS) are triggered by virus infection. However, a direct viral trigger of MS has not been identified. MS models in non-human primates suggest that lifelong asymptomatic infection with certain herpesviruses (e.g. cytomegalovirus) creates a repertoire of potentially autoreactive memory T cells. When these are exposed to antigens released after central nervous system injury as a consequence of an unknown pathogenic event, they are reactivated and induce autoimmune neurological disease. This re...
Source: Trends in Molecular Medicine - May 16, 2009 Category: Molecular Biology Authors: 't Hart BA, Hintzen RQ, Laman JD Tags: Trends Mol Med Source Type: journals

Apoptosis and colorectal cancer: implications for therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Colorectal cancer (CRC) is characterized by the partial suppression of apoptosis, which in turn gives tumours a selective advantage for survival and can cause current chemotherapy approaches to be ineffective. Recent progress in understanding the mechanisms of apoptosis in colorectal carcinogenesis has provided potential new targets for therapy. Here, we review recent studies of the regulation of apoptosis and its role in CRC initiation and progression, and we discuss the relationship between chemoresistance and the suppression of apoptosis. Recent progress in targeting apoptotic pathways and their regulators provide s...
Source: Trends in Molecular Medicine - May 1, 2009 Category: Molecular Biology Authors: Yang SY, Sales KM, Fuller B, Seifalian AM, Winslet MC Tags: Trends Mol Med Source Type: journals

Mechanotransduction in osteoblast regulation and bone disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Osteoblasts are key components of the bone multicellular unit and have a seminal role in bone remodeling, which is an essential function for the maintenance of the structural integrity and metabolic capacity of the skeleton. The coordinated function of skeletal cells is regulated by several hormones, growth factors and mechanical cues that act via interconnected signaling networks, resulting in the activation of specific transcription factors and, in turn, their target genes. Bone cells are responsive to mechanical stimuli and this is of pivotal importance in developing biomechanical strategies for the treatment of ost...
Source: Trends in Molecular Medicine - May 1, 2009 Category: Molecular Biology Authors: Papachroni KK, Karatzas DN, Papavassiliou KA, Basdra EK, Papavassiliou AG Tags: Trends Mol Med Source Type: journals

CD4 T-cell differentiation and inflammatory bowel disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Differentiation of naïve T cells leads to the generation of T-cell subsets, each possessing distinct cytokine expression profiles for serving different immune functions. Through the activation of separate signaling pathways, this process results in both differentiated helper T (Th) cells, termed Th1, Th2 and Th17, and induced regulatory T cells, which suppress Th cells. These different cells are important for combating infectious diseases and cancers; however, when aberrant, they can be responsible for chronic inflammatory diseases. One such disease is inflammatory bowel disease (IBD), in which each T-cell subset ...
Source: Trends in Molecular Medicine - May 1, 2009 Category: Molecular Biology Authors: Zenewicz LA, Antov A, Flavell RA Tags: Trends Mol Med Source Type: journals

The PI3K-PTEN tug-of-war, oxidative stress and retinal degeneration.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The retinal pigment epithelium (RPE) is indispensable for photoreceptor function, not only because it provides functional photopigments to photoreceptors, but also because it eliminates oxidatively damaged materials from photoreceptors. Maintaining homeostatic antioxidative programs that support a healthy RPE is therefore important for the normal functioning of the eye. These homeostatic mechanisms, however, often fail in aged RPE cells that have been exposed repeatedly to excessive oxidative stress. When RPE cells succumb to oxidative stress, their death contributes to the development of retinal degenerative diseases ...
Source: Trends in Molecular Medicine - May 1, 2009 Category: Molecular Biology Authors: Kang KH, Lemke G, Kim JW Tags: Trends Mol Med Source Type: journals

Regulation of the aging process by autophagy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Autophagy is involved in cellular protein and organelle degradation, which is mediated by the lysosomal pathway. Autophagocytosis has a key role in cellular housekeeping by removing damaged organelles. During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In Caenorhabditis elegans, there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Recent studies have revealed that the same signaling factors regulate both aging and autophagocytosis, thus highlighting the role of autophagy in the regulation of aging and age-related degenerative di...
Source: Trends in Molecular Medicine - May 1, 2009 Category: Molecular Biology Authors: Salminen A, Kaarniranta K Tags: Trends Mol Med Source Type: journals

Whole-genome association studies of sporadic amyotrophic lateral sclerosis: are retroelements involved?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Whole-genome association studies (WGASs) have identified single-nucleotide polymorphisms (SNPs) associated with sporadic amyotrophic lateral sclerosis (sALS). However, WGASs have so far produced results that are not consistent with those obtained from monogenic association studies focused on genes found to be relevant to ALS in functional biological studies. We propose that such inconsistencies might be at least partially alleviated by using approaches that integrate weakly associated SNPs. Several independent studies have detected abnormal reverse transcriptase (RT) activity in sALS patients, suggesting the involvemen...
Source: Trends in Molecular Medicine - April 1, 2009 Category: Molecular Biology Authors: Mougeot JL, Richardson-Milazi S, Brooks BR Tags: Trends Mol Med Source Type: journals

Endothelial progenitor cell-based neovascularization: implications for therapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ischemic cardiovascular events are a major cause of death globally. Endothelial progenitor cell (EPC)-based approaches can result in improvement of vascular perfusion and might offer clinical benefit. However, although functional improvement is observed, the lack of long-term engraftment of EPCs into neovessels has raised controversy regarding their mechanism of action. We and others have hypothesized that after ischemic injury, EPCs induce neovascularization through the secretion of cytokines and growth factors, which act in a paracrine fashion and induce sprouting angiogenesis by the surrounding endothelium. In this ...
Source: Trends in Molecular Medicine - March 18, 2009 Category: Molecular Biology Authors: Krenning G, van Luyn MJ, Harmsen MC Tags: Trends Mol Med Source Type: journals

Mitogen-activated protein kinases in male reproductive function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Recent studies have shown that male reproductive function is modulated via the mitogen-activated protein kinase (MAPK) cascade. The MAPK cascade is involved in numerous male reproductive processes, including spermatogenesis, sperm maturation and activation, capacitation and acrosome reaction, before fertilization of the oocyte. In this review, we discuss the latest findings in this rapidly developing field regarding the role of MAPK in male reproduction in animal models and in human spermatozoa in vitro. This research will facilitate the design of future studies in humans, although much work is needed before this infor...
Source: Trends in Molecular Medicine - March 18, 2009 Category: Molecular Biology Authors: Li MW, Mruk DD, Cheng CY Tags: Trends Mol Med Source Type: journals

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Bronchopulmonary dysplasia of the premature neonate and emphysema of the adult lung are common diseases that are characterized by increased airspace size and respiratory insufficiency and that presently lack efficient treatment. Although the former leads to impaired alveolar development and the latter to alveolar destruction, they have striking similarities in their pathophysiology, including the precipitating effect of oxidative stress, sustained inflammation, enhanced apoptosis, protease-antiprotease imbalance, elastic fiber deterioration and altered microvascularization. This review aims to comparatively analyze the...
Source: Trends in Molecular Medicine - March 18, 2009 Category: Molecular Biology Authors: Bourbon JR, Boucherat O, Boczkowski J, Crestani B, Delacourt C Tags: Trends Mol Med Source Type: journals

Degenerative diseases, oxidative stress and cytochrome c oxidase function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging and degenerative diseases are associated with increased levels of reactive oxygen species (ROS). ROS are mostly produced in mitochondria, and their levels increase with higher mitochondrial membrane potential. Cellular respiratory control is based on inhibition of respiration by high membrane potentials. However, we have described a second mechanism of respiratory control based on allosteric inhibition of cytochrome c oxidase (CcO), the terminal enzyme of the respiratory chain, at high ATP:ADP ratios. The mechanism is independent of membrane potential. We have proposed that feedback inhibition of CcO by ATP keeps...
Source: Trends in Molecular Medicine - March 18, 2009 Category: Molecular Biology Authors: Kadenbach B, Ramzan R, Vogt S Tags: Trends Mol Med Source Type: journals

Tau phosphorylation: the therapeutic challenge for neurodegenerative disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The microtubule-associated protein tau is integral to the pathogenesis of Alzheimer's disease (AD), as well as several related disorders, termed tauopathies, in which tau is deposited in affected brain regions. In the tauopathies, pathological tau is in an elevated state of phosphorylation and is aberrantly cleaved. It also exhibits abnormal conformations and becomes aggregated, resulting in neurofibrillary tau pathology. Recent evidence suggests that relatively early disease-associated changes in soluble tau proteins, including phosphorylation, are involved in the induction of neuronal death. Here, we summarize recent...
Source: Trends in Molecular Medicine - February 24, 2009 Category: Molecular Biology Authors: Hanger DP, Anderton BH, Noble W Tags: Trends Mol Med Source Type: journals

Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Zinc, which is essential for many cellular processes, is controlled by zinc transporters and through buffering by metallothioneins and glutathione. Although zinc is increasingly implicated in disease states, little is known about how zinc regulates cellular biochemical pathways. Recent seminal articles have revealed discrete zinc-trafficking pathways that are linked to signalling cascades, particularly those involving protein phosphatase inhibition and downstream activation of mitogen-activated protein kinases and tyrosine kinases. Here, we discuss the mechanisms of cellular zinc homeostasis, and we propose an importan...
Source: Trends in Molecular Medicine - February 24, 2009 Category: Molecular Biology Authors: Hogstrand C, Kille P, Nicholson RI, Taylor KM Tags: Trends Mol Med Source Type: journals

Uniparental disomy in cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Uniparental disomy (UPD) results when both copies of a chromosome pair originate from one parent. In humans, this might result in developmental disease or cancer due to either the production of homozygosity (caused by mutated or methylated genes or by microRNA sequences) or an aberrant pattern of imprinting. Constitutional UPD is associated with meiotic errors, resulting in developmental diseases, whereas acquired UPD probably occurs as a result of a mitotic error in somatic cells, which can be an important step in cancer development and progression. This review summarizes the mechanisms underlying UPD and their emergi...
Source: Trends in Molecular Medicine - February 24, 2009 Category: Molecular Biology Authors: Tuna M, Knuutila S, Mills GB Tags: Trends Mol Med Source Type: journals

Calcium signaling and neurodegenerative diseases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and spinocerebellar ataxias (SCAs), present an enormous medical, social, financial and scientific problem. Recent evidence indicates that neuronal calcium (Ca(2+)) signaling is abnormal in many of these disorders. Similar, but less severe, changes in neuronal Ca(2+) signaling occur as a result of the normal aging process. The role of aberrant neuronal Ca(2+) signaling in the pathogenesis of neurodegenerative disorders is discussed here. The potential utility of Ca(2+) b...
Source: Trends in Molecular Medicine - February 19, 2009 Category: Molecular Biology Authors: Bezprozvanny I Tags: Trends Mol Med Source Type: journals

When apoptosis meets autophagy: deciding cell fate after trauma and sepsis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Apoptotic cell death is considered to be an underlying mechanism in immunosuppression and multiple organ dysfunction after trauma-hemorrhage and sepsis. Although studied intensively over the last decade, the role of other cell death mechanisms under similar pathophysiological conditions has remained elusive. Recently, autophagy has emerged as an important mediator of programmed cell death pathways. Here, we review recent advances in our understanding of apoptosis and autophagy and the crosstalk between these processes. We explore the coexistence of these two processes and the effects of autophagy on apoptosis after tra...
Source: Trends in Molecular Medicine - February 19, 2009 Category: Molecular Biology Authors: Hsieh YC, Athar M, Chaudry IH Tags: Trends Mol Med Source Type: journals