Trends in Molecular Medicine (TRENDS MOL MED)

Publications in this journal

• Article: cAMP responsive element modulator: a critical regulator of cytokine production.

  Rauen T, Hedrich CM, Tenbrock K, Tsokos GC
  Trends in Molecular Medicine 03/2013;
• Article: IL-27 IN TUMOR IMMUNITY AND IMMUNOTHERAPY

  Murugaiyan Gopal, Bhaskar Saha
  Trends in Molecular Medicine 01/2013; 19(2):108-116.
• Article: Mechanotransduction in osteoblast regulation and bone disease.

  Katerina K Papachroni, Demetrios N Karatzas, Kostas A Papavassiliou, Efthimia K Basdra, Athanasios G Papavassiliou
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  ABSTRACT: 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 osteodegenerative diseases. Here, we review the molecular pathways and players activated by mechanical stimulation during osteoblastic growth, differentiation and activity in health, and consider the role of mechanostimulatory approaches in treating various bone pathophysiologies.
  Trends in Molecular Medicine 05/2009; 15(5):208-16.
• Article: Regulation of the aging process by autophagy.

  Antero Salminen, Kai Kaarniranta
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  ABSTRACT: 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 diseases. Here, we examine in detail the interactions of the signaling network involving longevity factors SIRT1, mTOR, FoxO3, NF-kappaB and p53 in the regulation of autophagy. We discuss the possibility that these well-known stress resistance and longevity factors regulate the aging process via autophagy.
  Trends in Molecular Medicine 05/2009; 15(5):217-24.
• Article: Degenerative diseases, oxidative stress and cytochrome c oxidase function.

  Bernhard Kadenbach, Rabia Ramzan, Sebastian Vogt
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  ABSTRACT: 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 the membrane potential and ROS production at low levels. Various forms of stress switch off allosteric ATP-inhibition via reversible dephosphorylation of CcO, resulting in increased membrane potential and cellular ROS levels. This mechanism is proposed to represent a missing molecular link between stress and degenerative diseases.
  Trends in Molecular Medicine 05/2009; 15(4):139-47.
• Article: Whole-genome association studies of sporadic amyotrophic lateral sclerosis: are retroelements involved?

  Jean-Luc Mougeot, Stephanie Richardson-Milazi, Benjamin Rix Brooks
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  ABSTRACT: 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 involvement of retroelements in ALS pathogenesis. Here, we discuss the functions of genes with SNPs or mutations in sALS and consider whether these might implicate the involvement of a putative retroelement associated with sALS pathogenesis. New experimental models for studying retroviral activation and the effects of xenobiotic agents in ALS will be needed to further investigate a potential role of retroelements in the etiology of sALS.
  Trends in Molecular Medicine 05/2009; 15(4):148-58.
• Article: Mitogen-activated protein kinases in male reproductive function.

  Michelle W M Li, Dolores D Mruk, C Yan Cheng
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  ABSTRACT: 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 information can be used to manage male infertility and environmental toxicant-induced testicular injury in men, such as blood-testis-barrier disruption.
  Trends in Molecular Medicine 05/2009; 15(4):159-68.
• Article: CD4 T-cell differentiation and inflammatory bowel disease.

  Lauren A Zenewicz, Andrey Antov, Richard A Flavell
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  ABSTRACT: 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 can have a role in disease. New studies highlight the importance of the recently identified Th17 subset in IBD. Therapeutics targeting these aberrant Th responses are already under development and hold promise for treating IBD and other chronic inflammatory diseases.
  Trends in Molecular Medicine 05/2009; 15(5):199-207.
• Article: Apoptosis and colorectal cancer: implications for therapy.

  Shi Yu Yang, Kevin M Sales, Barry Fuller, Alexander M Seifalian, Marc C Winslet
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  ABSTRACT: 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 strategies for the exploration of novel therapies for CRC.
  Trends in Molecular Medicine 05/2009; 15(5):225-33.
• Article: The PI3K-PTEN tug-of-war, oxidative stress and retinal degeneration.

  Kyung Hwa Kang, Greg Lemke, Jin Woo Kim
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  ABSTRACT: 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 such as age-related macular degeneration. Recent studies have highlighted the importance of reciprocal phosphoinositide signaling events orchestrated by phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) in the homeostatic programs that protect RPE cells against oxidative stress. Here, we discuss the role of PI3K signaling pathways in RPE cells and suggest that they might be crucial targets of oxidative molecules that initiate early pathological events in retinal degenerative diseases.
  Trends in Molecular Medicine 05/2009; 15(5):191-8.
• Article: Calcium signaling and neurodegenerative diseases.

  Ilya Bezprozvanny
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  ABSTRACT: 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 (Ca2+) signaling is abnormal in many of these disorders. Similar, but less severe, changes in neuronal Ca2+ signaling occur as a result of the normal aging process. The role of aberrant neuronal Ca2+ signaling in the pathogenesis of neurodegenerative disorders is discussed here. The potential utility of Ca2+ blockers for treatment of these disorders is also highlighted. It is reasoned that Ca2+ blockers will be most beneficial clinically when used in combination with other disease-specific therapeutic approaches.
  Trends in Molecular Medicine 03/2009; 15(3):89-100.
• Article: When apoptosis meets autophagy: deciding cell fate after trauma and sepsis.

  Ya-Ching Hsieh, Mohammad Athar, Irshad H Chaudry
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  ABSTRACT: 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 trauma-hemorrhage and sepsis. The inter-relationship between autophagy and apoptosis might unveil novel therapeutic approaches for the detection and treatment of trauma-hemorrhage and sepsis.
  Trends in Molecular Medicine 03/2009; 15(3):129-38.
• Article: Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation.

  C Hogstrand, P Kille, R I Nicholson, K M Taylor
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  ABSTRACT: 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 important role for the zinc transporter solute carrier family 39, member 7 (SLC39A7; commonly referred to as ZIP7). ZIP7 releases zinc from the endoplasmic reticulum and might be required for tyrosine kinase activation. These observations position ZIP7 at a critical node in zinc-mediated tyrosine kinase signalling and suggest that this protein might form a novel target for diseases such as cancer where prevention of tyrosine kinase activation would be therapeutically advantageous.
  Trends in Molecular Medicine 03/2009; 15(3):101-11.
• Article: Uniparental disomy in cancer.

  Musaffe Tuna, Sakari Knuutila, Gordon B Mills
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  ABSTRACT: 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 emerging association with cancer.
  Trends in Molecular Medicine 03/2009; 15(3):120-8.
• Article: C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress.

  Massimo Cugno, Andrea Zanichelli, Fabrizio Foieni, Sonia Caccia, Marco Cicardi
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  ABSTRACT: C1 inhibitor (C1-INH, also known as SERPING1) can be deficient in plasma as a result of genetic or acquired conditions, and this causes an episodic, local increase in vascular permeability in the subcutaneous and submucosal layers, identified as angioedema (hereditary or acquired). Bradykinin, the mediator of the increase in vascular permeability, is released on inappropriate activation of the contact system, which is controlled by C1 inhibitor. Therapy aims to reverse or prevent angioedema. Advances in understanding the complex effects of C1-INH deficiency at the molecular level have led to new molecular-targeted approaches. Three new treatments, an inhibitor of kallikrein to prevent bradykinin release, an antagonist of the bradykinin receptor to prevent its action and a recombinant human C1-INH produced in transgenic animals, are under clinical evaluation currently. Here, we review the molecular mechanisms underlying angioedema due to C1-inhibitor deficiency and clinical progress using molecular-targeted interventions.
  Trends in Molecular Medicine 02/2009; 15(2):69-78.
• Article: TGF-beta and kynurenines as the key to infectious tolerance.

  Maria L Belladonna, Ciriana Orabona, Ursula Grohmann, Paolo Puccetti
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  ABSTRACT: The maintenance of self-tolerance is an integral part of the immune surveillance process, in which cytokines act as master regulators of a complex network involving multiple cell types. On such cytokines, transforming growth factor-beta (TGF-beta) exerts a suppressive control over immune reactivity, which so far appears to be mostly confined to the T-cell compartment. Recently, dendritic cells (DCs) have been found to be both an early source and a target of TGF-beta actions. In these cells, autocrine, paracrine and T-cell-derived TGF-beta activates the tolerogenic pathway of tryptophan catabolism - mediated by indoleamine 2,3-dioxygenase (IDO) - resulting in a burst of regulatory kynurenines that contribute to establishing a state of 'infectious tolerance'. Current molecular insights suggest a synergistic potential for TGF-beta and IDO in physiologically or therapeutically opposing human pathologies sustained by over-reacting immune responses.
  Trends in Molecular Medicine 02/2009; 15(2):41-9.
• Article: Induced pluripotent stem cells: current progress and potential for regenerative medicine.

  Giovanni Amabile, Alexander Meissner
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  ABSTRACT: Lineage-restricted cells can be reprogrammed to a pluripotent state through overexpression of defined transcription factors. Here, we summarize recent progress in the direct reprogramming field and discuss data comparing embryonic stem (ES) and induced pluripotent stem (iPS) cells. Results from many independent groups suggest that mouse and human iPS cells, once established, generally exhibit a normal karyotype, are transcriptionally and epigenetically similar to ES cells and maintain the potential to differentiate into derivatives of all germ layers. Recent developments provide optimism that safe, viral-free human iPS cells could be derived routinely in the near future. An important next step will be to identify ways of assessing which iPS cell lines are sufficiently reprogrammed and safe to use for therapeutic applications. The approach of generating patient-specific pluripotent cells will undoubtedly transform regenerative medicine in many ways.
  Trends in Molecular Medicine 02/2009; 15(2):59-68.