Drug discovery today. Disease mechanisms最新文献

Cathelicidin antimicrobial peptide is an important mediator of the innate immune response. In addition to its potent antimicrobial activity, cathelicidin has been shown to have chemoattractant and angiogenic properties. Recent research has demonstrated that, in addition to its aforementioned functions, cathelicidin plays an important role in the complex pathogenesis of several chronic inflammatory skin diseases. This review will present a concise overview of the role of cathelicidin in infection and in the development of atopic dermatitis, psoriasis and rosacea. This understanding will direct future research efforts to identify therapeutic approaches that use cathelicidin as a novel drug itself, or aim to modify its expression and regulation.

Centrosomes and cilia are conserved microtubule-based organelles whose structure and function depend on cell cycle stages. In dividing cells, centrosomes organize mitotic spindle poles, while in differentiating cells, centrosomes template ciliogenesis. Classically, this functional dichotomy has been attributed to regulation by cell cycle-dependent post-translational modifications, and recently PLK1, Nek2, Aurora A, and tubulin deacetylase were implicated in regulating the transition from cilia to centrosome. However, other recent studies suggest that tubulin dimers, the core structural components of centrosomes and cilia, also have a regulatory role. These regulatory mechanisms can be a target for chemotherapeutic intervention.

The primary cilium is a well-established target in the pathogenesis of numerous developmental and chronic disorders, and more recently is attracting interest as a structure relevant to cancer. Here we discuss mechanisms by which changes in cilia can contribute to the formation and growth of tumors. We emphasize the cancer-relevance of cilia-dependent signaling pathways and proteins, including mTOR, VHL, TSC, WNT, Aurora-A, NEDD9 and Hedgehog, and highlight the emerging role of ciliary dysfunction in renal cell carcinoma, medulloblastoma and breast cancer.

Our skin is home to a rich community of microorganisms. Recent advances in sequencing technology have allowed more accurate enumeration of these human-associated microbiota and investigation of their genomic content. Staphylococcus, Corynebacterium and Propionibacterium represent the dominant bacterial genera on skin and illustrate how bacteria adapt to life in this harsh environment and also provide us with unique benefits. In healthy states, our skin peacefully co-exists with commensal bacteria while fending off potentially dangerous invaders. Disruption of this equilibrium, termed ‘dysbiosis’, can result from changes in the composition of our skin bacteria, an altered immune response to them, or both and may be a driving factor in certain types of inflammatory skin disease. Engineering topical therapeutics to favorably influence the composition of our skin flora and optimize interactions with them represents a real therapeutic opportunity for the field of dermatology and warrants additional investigation into skin microbial ecology and disease mechanisms related to host–microbe dysbiosis.

Polycystic diseases affect approximately 1/1000 and are important causes of kidney failure. No therapies presently are in clinical practice that can prevent disease progression. Multiple mouse models have been produced for the genetic forms of the disease that most commonly affect humans. In this report, we review recent progress in the field and describe some of the outstanding challenges.

Venous leg ulcers are a common complication of venous insufficiency, and result in significant patient morbidity and socioeconomic costs related to care. Patients with venous leg ulcers often fail to achieve complete healing with standard of care treatments even with the addition of the numerous adjuvant therapies available. To gain insight into new treatment directions, we reviewed current clinical trials evaluating the efficacy of novel therapeutics in the treatment of venous ulcers.

Insulin/IGF-1 signaling plays a central role in control of cellular metabolism and survival, while insulin receptor substrate (IRS) protein-1 and -2 and downstream PI-3 kinase→Akt→Foxo1 signaling cascade play key roles in many functions of insulin/IGF-1. Dysregulation of this branch of signaling cascades may provide a mechanism for insulin resistance as we observed in cells, animals, and even humans. Targeting this branch of IRS→Foxo1 signaling may provide us with fundamental strategies for drug development in the future.

Obesity is recognized as an independent and increasingly prevalent risk factor for cardiovascular morbidity and mortality. This stems in part from the contribution of obesity toward insulin resistance and diabetes, which associate with premature atherosclerosis, enhanced thrombogenicity and activation of systemic inflammatory programs with resultant cardiovascular dysfunction. This review will focus on the more direct mechanisms underpinning obesity-associated cardiac pathophysiology including the metabolic consequences of lipid accumulation in the myocardium and the consequences of direct systemic effects of lipid toxicity. Furthermore, there is growing recognition that metabolic intermediates, which may be perturbed with caloric excess, may play an important role in intracellular signal transduction and on the post-translational control of metabolic functioning within the heart. As strategies to reverse obesity appear to have ameliorative cardiac effects, surgical and therapeutic approaches to facilitate weight reduction will also be discussed.

Obesity and the intimately associated scourge of type 2 diabetes are global pandemics whose prevalence has increased exponentially, particularly in affluent economies. Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of excess adiposity is now the principal cause of chronic liver disease in many countries. Consistent with its pivotal role, the majority of obese patients have concomitant NAFLD. However, while obesity is a risk factor for disease progression, only a minority with NAFLD develop liver-related complications. This reflects the complex interplay of factors that modulate NAFLD progression. Despite the focus on liver-related outcomes in patients with NAFLD, the majority succumb to cardiovascular disease and to cancer. Interestingly, recent epidemiological data suggest that the presence of hepatic steatosis is independently associated with cardiovascular and cancer risk. In this article we describe the pathogenic pathways that link obesity to NAFLD progression and how liver disease evolution can result in pro-atherosclerotic and oncogenic systemic dysfunction.

Obesity epidemics affect 35.7% of adults and approximately 17% of children in the United States. Obesity has been associated with several health disorders such as type 2 diabetes, cardiovascular diseases, fatty liver disease, and certain forms of cancer. Medical costs associated with obesity were estimated at $147 billion in 2008. Chronic tissue inflammation, particularly in adipose tissue, has been considered as a key underlying mechanism for the development of obesity-related metabolic syndrome. In this review, we discuss the recent progress in the field of metabolic inflammation and the potential implication of anti-inflammation approaches as therapeutic interventions for treating obesity-related metabolic disorders.