RESUMEN
The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Terapia Molecular Dirigida , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Animales , Humanos , Modelos BiológicosRESUMEN
Multiple myeloma (MM) is a hematologic malignancy characterized as an abnormal proliferation and invasion of plasma cells into the bone marrow. Toll-like receptors (ТLRs) connect the innate and adaptive immune responses and represent a significant and potentially linking element between inflammation and cancer. When TLRs bind to their ligands, they trigger two major signaling pathways such that both share overlapping downstream signals: one is a myeloid differentiation primary response 88 (MyD88)-dependent production and activation of nuclear factor-κB, whereas the other is a MyD88-independent production of type-I interferon. Whereas the MyD88 pathway results in proinflammatory cytokine production, the other pathway stimulates cell proliferation. Dysregulations of these pathways may eventually lead to abnormal cell proliferation and MM. Despite recent biomedical advances, MM continues to be an incurable disease. There are an increasing number of TLR-based therapeutic approaches currently being tested in a number of preclinical and clinical studies. We here attempt to outline in detail the currently available information on TLRs in various types of cancer.