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Trends in Molecular Medicine

Nadeem O Kaakoush, Margaret J Morris
Poor diets are associated with obesity and a decline in cognitive function. Flavonoids are plant compounds that have been associated with improved metabolic parameters in obesity and reversal of cognitive decline. Given that microbial flavonoid conversion is important for bioactivity, flavonoid-derived neuroactive compounds may be functionally crucial in the gut microbiome-brain axis.
March 17, 2017: Trends in Molecular Medicine
Nadiya Khyzha, Azad Alizada, Michael D Wilson, Jason E Fish
Atherosclerosis is a vascular pathology characterized by inflammation and plaque build-up within arterial vessel walls. Vessel occlusion, often occurring after plaque rupture, can result in myocardial and cerebral infarction. Epigenetic changes are increasingly being associated with atherosclerosis and are of interest from both therapeutic and biomarker perspectives. Emerging genomic approaches that profile DNA methylation, chromatin accessibility, post-translational histone modifications, transcription factor binding, and RNA expression in low or single cell populations are poised to enhance our spatiotemporal understanding of atherogenesis...
March 10, 2017: Trends in Molecular Medicine
David Millrine, Tadamitsu Kishimoto
Thalidomide and its derivatives are immunomodulatory drugs (IMiDs) known for their sedative, teratogenic, anti-angiogenic, and anti-inflammatory properties. Commonly used in the treatment of cancers such as multiple myeloma and myelodysplastic syndrome (MDS), IMiDs have also been used in the treatment of an inflammatory skin pathology associated with Hansen's disease/leprosy. They have also shown promise in the treatment of autoimmune disorders including systemic lupus erythmatosus (SLE) and inflammatory bowel disease (IBD)...
March 9, 2017: Trends in Molecular Medicine
Robert A H van de Ven, Daniel Santos, Marcia C Haigis
Advancing age is the major risk factor for the development of chronic diseases and is accompanied by changes in metabolic processes and mitochondrial dysfunction. Mitochondrial sirtuins (SIRT3-5) are part of the sirtuin family of NAD(+)-dependent deacylases and ADP-ribosyl transferases. The dependence on NAD(+) links sirtuin enzymatic activity to the metabolic state of the cell, poising them as stress sensors. Recent insights have revealed that SIRT3-5 orchestrate stress responses through coordinated regulation of substrate clusters rather than of a few key metabolic enzymes...
March 9, 2017: Trends in Molecular Medicine
Ole Haagen Nielsen, Yuan Li, Bengt Johansson-Lindbom, Mehmet Coskun
An unmet medical need exists for the development of targeted therapies for the treatment of inflammatory bowel disease (IBD) with easily administered and stable oral drugs, particularly as most patients on biologics [i.e., tumor necrosis factor (TNF) inhibitors and anti-integrins] are either primary non-responders or lose responsiveness during maintenance treatment. A new class of small molecules, sphingosine-1-phosphate (S1P) receptor modulators, has recently shown efficacy in IBD. Here we provide an overview of the mechanism of action of this novel treatment principle in the context of intestinal inflammation...
March 7, 2017: Trends in Molecular Medicine
Alexandros G Georgakilas, Olga A Martin, William M Bonner
Upon DNA damage or other stressors, the tumor suppressor p53 is activated, leading to transient expression of the cyclin-dependent kinase inhibitor (CKI) p21. This either triggers momentary G1 cell cycle arrest or leads to a chronic state of senescence or apoptosis, a form of genome guardianship. In the clinic, the presence of p21 has been considered an indicator of wildtype p53 activity. However, recent evidence suggests that p21 also acts as an oncogenic factor in a p53-deficient environment. Here, we discuss the controversial aspects of the two-faced involvement of p21 in cancer and speculate on how this new information may increase our understanding of its role in cancer pathogenesis...
March 6, 2017: Trends in Molecular Medicine
Daniel J Woodsworth, Robert A Holt
The diversity and specialization found in biological molecules, pathways, and cells is staggering, and should be exploited for therapeutic use. Through evolution these biological systems have attained a level of functionality that would be impossible to recapitulate with de novo assembly. To adapt these systems for therapeutic applications it will be often necessary to re-engineer molecules and pathways to yield novel sensory, control, and effector modules for insertion into existing, specialized cellular chassis...
January 24, 2017: Trends in Molecular Medicine
Sanjeev Mariathasan, Man-Wah Tan
Antibodies are potent components of the immune repertoire and have been successfully exploited to treat bacterial infections. Recently an antibody-antibiotic conjugate (AAC) that combines key attributes of an antibody and antibiotic has been shown to be efficacious against Staphylococcus aureus infection. An AAC has three components: an antibiotic payload to kill bacteria, an antibody to target delivery of the payload to bacteria, and a linker attaching the payload to the antibody. With increasing understanding of the biology and pathophysiology of S...
January 23, 2017: Trends in Molecular Medicine
Adrian Liston, John A Todd, Vasiliki Lagou
Type 1 and type 2 diabetes are distinct clinical entities primarily driven by autoimmunity and metabolic dysfunction, respectively. However, there is a growing appreciation that they may share an etiopathological factor, namely the role of variation in beta-cell sensitivity to stress factors. Increased sensitivity increases the risk of beta-cell death or insulin secretion dysfunction. The beta-cell fragility model proposes that this variation contributes to the risk of developing either type 1 or type 2 diabetes, in the presence of immunological and/or metabolic stress factors...
January 20, 2017: Trends in Molecular Medicine
Nicoletta Plotegher, Michael R Duchen
Lysosomal storage disorders (LSDs) are rare inherited debilitating and often fatal disorders. Caused by mutations affecting lysosomal proteins, LSDs are characterized by the accumulation of undegraded material in lysosomes and by lysosomal dysfunction. Although LSDs are multisystemic diseases, the majority display neurologic symptoms and neurodegeneration. Only recently has a role emerged for mitochondrial dysfunction in the pathophysiology of LSDs, suggesting an impact of lysosomal dysfunction on mitochondria...
January 19, 2017: Trends in Molecular Medicine
Meghana N Patel, Richard G Carroll, Silvia Galván-Peña, Evanna L Mills, Robin Olden, Martha Triantafilou, Amaya I Wolf, Clare E Bryant, Kathy Triantafilou, Seth L Masters
The inflammasome is a cytoplasmic protein complex that processes interleukins (IL)-1β and IL-18, and drives a form of cell death known as pyroptosis. Oligomerization of this complex is actually the second step of activation, and a priming step must occur first. This involves transcriptional upregulation of pro-IL-1β, inflammasome sensor NLRP3, or the non-canonical inflammasome sensor caspase-11. An additional aspect of priming is the post-translational modification of particular inflammasome constituents...
January 18, 2017: Trends in Molecular Medicine
Julia Brangsch, Carolin Reimann, Federico Collettini, Ralf Buchert, René M Botnar, Marcus R Makowski
Abdominal aortic aneurysms (AAAs) represent a vascular disease with severe complications. AAAs are currently the overall 10th leading cause of death in western countries and their incidence is rising. Although different diagnostic techniques are currently available in clinical practice, including ultrasound (US), magnetic resonance imaging (MRI), and computed tomography (CT), imaging-based prediction of life-threatening complications such as aneurysm-rupture remains challenging. Molecular imaging provides a novel diagnostic approach for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level...
January 16, 2017: Trends in Molecular Medicine
Paula Gonzalez-Figueroa, Jonathan A Roco, Carola G Vinuesa
Current HIV vaccines are poor inducers of neutralizing antibodies (nAbs). A recent study in Cell Reports used serial fine-needle aspirates from rhesus macaque lymph nodes following HIV-1 surface envelope glycoprotein (Env) trimer immunization, generating a substantial production of HIV-1 nAbs. A remarkable correlation was found between antibody titers and a high frequency and ratio of germinal center B and T follicular helper (TFH) lymphocytes.
January 11, 2017: Trends in Molecular Medicine
Gabriela Brumatti, Najoua Lalaoui, Andrew H Wei, John Silke
Malignant cells must circumvent endogenous cell death pathways to survive and develop into cancers. Acquired cell death resistance also sets up malignant cells to survive anticancer therapies. Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by high relapse rate and resistance to cytotoxic therapies. Recent collaborative profiling projects have led to a greater understanding of the 'fearful symmetry' of the genomic landscape of AML, and point to the development of novel potential therapies that can overcome factors linked to chemoresistance...
March 2017: Trends in Molecular Medicine
Ryuji Morizane, Joseph V Bonventre
Human pluripotent stem cells (hPSCs) are attractive sources for regenerative medicine and disease modeling in vitro. Directed hPSC differentiation approaches have derived from knowledge of cell development in vivo rather than from stochastic cell differentiation. Moreover, there has been great success in the generation of 3D organ-buds termed 'organoids' from hPSCs; these consist of a variety of cell types in vitro that mimic organs in vivo. The organoid bears great potential in the study of human diseases in vitro, especially when combined with CRISPR/Cas9-based genome-editing...
March 2017: Trends in Molecular Medicine
David Sebastián, Manuel Palacín, Antonio Zorzano
Aging is associated with a decline in mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these mitochondrial alterations and the role of the latter in aging are still not fully understood. Mitochondrial dynamics is a key process regulating mitochondrial function and quality. Altered expression of some mitochondrial dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans, mice, and humans...
March 2017: Trends in Molecular Medicine
Akiko Iwasaki
This review highlights recent advances in how the innate and adaptive immune systems control the blood-brain barrier (BBB) and the blood-nerve barrier (BNB). Interferons and TAM receptors play key roles in innate immune control of the BBB. Cells of the adaptive immune system, particularly CD4(+) T cells, take distinct routes to enter neural tissues and mediate immune surveillance. Furthermore, T cell-mediated opening of the BBB and the BNB is crucial to allow antibody access and thereby block the replication of neurotropic viruses...
March 2017: Trends in Molecular Medicine
Ans De Beuckelaer, Johan Grooten, Stefaan De Koker
mRNA vaccines have emerged as potent tools to elicit antitumor T cell immunity. They are characterized by a strong induction of type I interferons (IFNs), potent inflammatory cytokines affecting T cell differentiation and survival. Recent reports have attributed opposing roles for type I IFNs in modulating CD8+ T cell immunity to mRNA vaccines, from profoundly stimulatory to strongly inhibitory. The mechanisms behind this duality are unclear. Disentangling the factors governing the beneficial or detrimental impact of type I IFNs on CD8+ T cell responses is vital to the design of mRNA vaccines of increased potency...
March 2017: Trends in Molecular Medicine
Qi Yang, Peng Hou
In a recent article published in Cancer Cell, Cantelmo et al. showed that inhibition of endothelium glycolysis by targeting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) significantly impaired tumor metastasis by normalizing tumor vessels. In addition, as a promising therapeutic strategy, tumor vessel normalization by PFKFB3 blockade also improved the delivery and efficacy of chemotherapy.
March 2017: Trends in Molecular Medicine
Thomas Simon, Teresa Gagliano, Georgios Giamas
Over recent decades anti-angiogenic therapies (AATs) have produced promising results in the treatment of different malignancies. Unfortunately, resistance often develops and patients ultimately relapse. In an attempt to elucidate the causes of recurrence, most studies have focused on tumor responses to hypoxic conditions induced by AAT. However, strategies targeting these mechanisms of resistance are still failing to improve treatments. Furthermore, a potential direct impact of AAT on tumor cells cannot be overlooked...
March 2017: Trends in Molecular Medicine
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