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Trends in Molecular Medicine

Tinneke Delvaeye, Peter Vandenabeele, Geert Bultynck, Luc Leybaert, Dmitri V Krysko
Connexins, in particular connexin 43 (Cx43), function as gap junction channels (GJCs) and hemichannels (HCs). Only recently, specific tools have been developed to study their pleiotropic functions. Based on various protein interaction sites, distinct connexin-mimetic peptides have been established that enable discrimination between the function of HCs and GJCs. Although the precise mechanism of action of most of these peptides is still a matter of debate, an increasing number of studies report on important effects of those compounds in disease models...
November 10, 2018: Trends in Molecular Medicine
Peppi Koivunen, Thomas Kietzmann
Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs or EglNs) are enzymes that act as cellular oxygen sensors. Inhibition of HIF-P4Hs leads to stabilization of hypoxia-inducible transcription factors (HIFs), which initiates a gene expression program that allows organisms to cope with low oxygen levels and restore tissue oxygenation. This involves, for example, upregulation of erythropoiesis and angiogenesis, modulation of inflammatory responses, and reprogramming of metabolism. Currently, several pharmacological HIF-P4H inhibitors are in clinical trials mainly for renal anemia...
October 31, 2018: Trends in Molecular Medicine
Cleber A Trujillo, Alysson R Muotri
Brain organoids are 3D self-assembled structures composed of hundreds of thousands to millions of cells that resemble the cellular organization and transcriptional and epigenetic signature of a developing human brain. Advancements using brain organoids have been made to elucidate the genetic basis of certain neurodevelopmental disorders, such as microcephaly and autism; and to investigate the impact of environmental factors to the brain, such as during Zika virus infection. It remains to be explored how far brain organoids can functionally mature and process external information...
October 27, 2018: Trends in Molecular Medicine
Allison Soung, Robyn S Klein
Neurotropic RNA virus infections cause a major neurological disease burden. Due to the morbidity and mortality rates of viral encephalitides worldwide, there is a need to develop clinical treatments. Features of the central nervous system (CNS), including interconnected cell types and limited regeneration, provide unique challenges. Viral encephalitis and antiviral immunity can disrupt the CNS environment, leaving patients with poor neurological outcomes despite virologic control. The cellular mechanism(s) underlying neurological recovery are not fully understood, but involve neuroimmune interactions that, until recently, primarily focused on microglia...
October 9, 2018: Trends in Molecular Medicine
Johannes Lehmann, Marjolein P Baar, Peter L J de Keizer
Senescent cells drive ageing and the associated loss in health and lifespan. Whether this is mediated by systemic signalling remained unclear. Recently, Xu et al. [1] (Nat. Med. 2018;24:1246-1256) answered this question by injecting senescent cells into young mice and observing a long-lasting increase in frailty and mortality.
October 3, 2018: Trends in Molecular Medicine
Mikel D Haggadone, Marc Peters-Golden
Extracellular vesicles (EVs) are increasingly appreciated as important vectors of information transmission between cells. Most research on EVs has emphasized their roles in inflammatory and pathologic conditions, and in the airways and alveoli, EV secretion by various cell types is implicated in various forms of lung disease. However, recent evidence also demonstrates a homeostatic role for lung EVs by mediating transmission of anti-inflammatory signals between alveolar macrophages and lung epithelial cells...
September 20, 2018: Trends in Molecular Medicine
Ciriana Orabona, Giada Mondanelli, Paolo Puccetti, Ursula Grohmann
Although significant progress has been made in understanding autoimmunity, no immunotherapy to effectively halt immune-mediated destruction of β cells in type 1 diabetes (T1D) is currently available. For successful immunotherapy it will be necessary to identify novel drug targets as well as robust immunologic biomarkers to predict disease heterogeneity and patient responsiveness. Inhibition of immune checkpoint mechanisms represents a novel and effective strategy in tumor immunotherapy. Because they are fundamental to rewiring immune circuits, the underlying mechanisms could be therapeutically enhanced and used as biomarkers in T1D...
September 17, 2018: Trends in Molecular Medicine
Nadya Lumelsky, Morgan O'Hayre, Preethi Chander, Lillian Shum, Martha J Somerman
The promise of tissue engineering and regenerative medicine to reduce the burden of disease and improve quality of life are widely acknowledged. Traditional tissue engineering and regenerative medicine approaches rely on generation of tissue constructs in vitro for subsequent transplantation or injection of exogenously manipulated cells into a host. While promising, few such therapies have succeeded in clinical practice. Here, we propose that recent advances in stem cell and developmental biology, immunology, bioengineering, and material sciences, position us to develop a new generation of in vivo regenerative medicine therapies, which we term autotherapies...
September 10, 2018: Trends in Molecular Medicine
Paola Dazzan, Montserrat Fusté, William Davies
Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets...
November 2018: Trends in Molecular Medicine
Arantzazu Alfranca, Miguel R Campanero, Juan Miguel Redondo
Lentiviral vectors (LVs) transduce quiescent cells and provide stable integration to maintain transgene expression. Several approaches have been adopted to optimize LV safety profiles. Similarly, LV targeting has been tailored through strategies including the modification of envelope components, the use of specific regulatory elements, and the selection of appropriate administration routes. Models of aortic disease based on a single injection of pleiotropic LVs have been developed that efficiently transduce the three aorta layers in wild type mice...
October 2018: Trends in Molecular Medicine
Ralitsa R Madsen, Bart Vanhaesebroeck, Robert K Semple
PIK3CA is one of the most commonly mutated genes in solid cancers. PIK3CA mutations are also found in benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). As in cancer, PIK3CA mutations in PROS arise postzygotically, but unlike in cancer, these mutations arise during embryonic development, with their timing and location critically influencing the resulting disease phenotype. Recent evidence indicates that phosphoinositide 3-kinase (PI3K) pathway inhibitors undergoing trials in cancer can provide a therapy for PROS...
October 2018: Trends in Molecular Medicine
Yu Sun, Jean-Philippe Coppé, Eric W-F Lam
Cellular senescence is a process that results in irreversible cell-cycle arrest, and is thought to be an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic and signaling features, together referred to as the senescence-associated secretory phenotype (SASP). The SASP is implicated in several aging-related pathologies, including various malignancies. Accumulating evidence argues that cellular senescence acts as a double-edged sword in human cancer, and new agents and innovative strategies to tackle senescent cells are in development pipelines to counter the adverse effects of cellular senescence in the clinic...
October 2018: Trends in Molecular Medicine
Rajashekar Varma Kadumuri, Sarath Chandra Janga
Innovations in epitranscriptomics have resulted in the identification of more than 160 RNA modifications to date. These developments, together with the recent discovery of writers, readers, and erasers of modifications occurring across a wide range of RNAs and tissue types, have led to a surge in integrative approaches for transcriptome-wide mapping of modifications and protein-RNA interaction profiles of epitranscriptome players. RNA modification maps and crosstalk between them have begun to elucidate the role of modifications as signaling switches, entertaining the notion of an epitranscriptomic code as a driver of the post-transcriptional fate of RNA...
October 2018: Trends in Molecular Medicine
Madalina E Carter-Timofte, Søren R Paludan, Trine H Mogensen
In most individuals, varicella zoster virus (VZV) causes varicella upon primary infection and zoster during reactivation. However, in a subset of individuals, VZV may cause severe disease, including encephalitis. Host genetics is believed to be the main determinant of exacerbated disease manifestations. Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity...
October 2018: Trends in Molecular Medicine
Dana V Foss, Ross C Wilson
Despite the unparalleled therapeutic promise of genome editing, its curative power is currently limited by the substantial difficulty in delivering DNA-cutting enzymes to the cells in need of correction. A recent study demonstrates the potential for the delivery of pre-assembled genome-editing enzymes in the form of ribonucleoprotein complexes, which were used to rescue a mouse model of fragile X syndrome (FXS).
October 2018: Trends in Molecular Medicine
Luca Peruzzotti-Jametti, Stefano Pluchino
The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation...
October 2018: Trends in Molecular Medicine
Aislyn Schalck, Chantale Bernatchez, Nicholas Navin
The role of tissue-resident memory T (TRM ) cells in breast cancer progression has been difficult to study. Savas et al. [1] (Nat. Med. 2018;24:986-993) used single-cell RNA sequencing to identify TRM cells in triple-negative breast cancer patients and demonstrated their prognostic value for predicting survival.
October 2018: Trends in Molecular Medicine
Mohamad Hamieh, Michel Sadelain
In a recent study, Fraietta and colleagues identified chimeric antigen receptor (CAR) T cell biomarkers that may predict the success or failure of CAR therapy in patients with refractory chronic lymphoblastic leukemia (CLL). These findings open new prospects for improving T cell product manufacturing and the management of patients with CLL undergoing T cell-based therapies.
September 2018: Trends in Molecular Medicine
Jan M Deussing, Eduardo Arzt
Depression is a prime contributor to global disease burden with 300 million affected patients worldwide. The persistent lack of progress with regards to pharmacotherapy stands in stark contrast to the pandemic magnitude of the disease. Alterations of inflammatory pathways in depressed patients, including altered circulating pro-inflammatory cytokines, have been put forward as a potential pathophysiological mechanism. The P2X7 receptor (P2X7R) plays an important role regulating the release of interleukin-1β and other cytokines...
September 2018: Trends in Molecular Medicine
Mark C de Gooijer, Miriam Guillén Navarro, Rene Bernards, Thomas Wurdinger, Olaf van Tellingen
Glioblastoma is a highly aggressive brain tumor that is characterized by its unparalleled invasiveness. Invasive glioblastoma cells not only escape surgery and focal therapies but also are more resistant to current radio- and chemo-therapeutic approaches. Thus, any curative therapy for this deadly disease likely should include treatment strategies that interfere with glioblastoma invasiveness. Understanding glioblastoma invasion mechanisms is therefore critical. We discuss the strengths and weaknesses of various glioblastoma invasion models and conclude that robust experimental evidence has been obtained for a pro-invasive role of Ephrin receptors, Rho GTPases, and casein kinase 2 (CK2)...
September 2018: Trends in Molecular Medicine
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