During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy.
Janet L. Crane, Xu Cao
The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics.
Nathaniel M. Weathington, Rama K. Mallampalli
Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes.
Grit S. Herter-Sprie, Andrew L. Kung, Kwok-Kin Wong
Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.
Jonathan Welti, Sonja Loges, Stefanie Dimmeler, Peter Carmeliet
Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. Regular exercise and calorie restriction have long been known to increase insulin sensitivity and decrease the prevalence of these disorders. The subsequent identification of AMP-activated protein kinase (AMPK) and its activation by exercise and fuel deprivation have led to studies of the effects of AMPK on both IR and metabolic syndrome–related diseases. In this review, we evaluate this body of literature, with special emphasis on the hypothesis that dysregulation of AMPK is both a pathogenic factor for these disorders in humans and a target for their prevention and therapy.
Neil B. Ruderman, David Carling, Marc Prentki, José M. Cacicedo
Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple proteins, including hemojuvelin, bone morphogenetic protein 6 (BMP6), hereditary hemochromatosis protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload.
Ningning Zhao, An-Sheng Zhang, Caroline A. Enns
Many neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and frontotemporal dementia, are proteinopathies that are associated with the aggregation and accumulation of misfolded proteins. While remarkable progress has been made in understanding the triggers of these conditions, several challenges have hampered the translation of preclinical therapies targeting pathways downstream of the initiating proteinopathies. Clinical trials in symptomatic patients using therapies directed toward initiating trigger events have met with little success, prompting concerns that such therapeutics may be of limited efficacy when used in advanced stages of the disease rather than as prophylactics. Herein, we discuss gaps in our understanding of the pathological processes downstream of the trigger and potential strategies to identify common features of the downstream degenerative cascade in multiple CNS proteinopathies, which could potentially lead to the development of common therapeutic targets for multiple disorders.
Todd E. Golde, David R. Borchelt, Benoit I. Giasson, Jada Lewis
The classical Mendelian genetic perspective has failed to adequately explain the biology and genetics of common metabolic and degenerative diseases. This is because these diseases are primarily systemic bioenergetic diseases, and the most important energy genes are located in the cytoplasmic mitochondrial DNA (mtDNA). Therefore, to understand these “complex” diseases, we must investigate their bioenergetic pathophysiology and consider the genetics of the thousands of copies of maternally inherited mtDNA, the more than 1,000 nuclear DNA (nDNA) bioenergetic genes, and the epigenomic and signal transduction systems that coordinate these dispersed elements of the mitochondrial genome.
Douglas C. Wallace
Tregs have been implicated in control of homeostasis in the immune system and beyond. These cells restrain inflammatory responses to self antigens, commensal microorganisms, allergens, and pathogens and adapt their homeostatic and functional capabilities to a particular environment. In this review, we discuss a general model of integration of environmental cues by Tregs in which specialized Treg homeostatic, migratory, and suppression programs are established in dynamically changing inflammatory environments by maintaining an optimal threshold of activation of transcription factors involved in regulation of the corresponding type of effector immune responses.
Ashutosh Chaudhry, Alexander Y. Rudensky
Alzheimer’s disease (AD) and diabetes are currently considered among the top threats to human health worldwide. Intriguingly, a connection between these diseases has been established during the past decade, since insulin resistance, a hallmark of type 2 diabetes, also develops in Alzheimer brains. In this article, the molecular and cellular mechanisms underlying defective brain insulin signaling in AD are discussed, with emphasis on evidence that Alzheimer’s and diabetes share common inflammatory signaling pathways. I put forward here a hypothesis on how a cross-talk between peripheral tissues and the brain might influence the development of AD, and highlight important unanswered questions in the field. Furthermore, I discuss a rational basis for the use of antidiabetic agents as novel and potentially effective therapeutics in AD.
Fernanda G. De Felice
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