Drug discovery today. Disease mechanisms最新文献

The story of oxytocin (OXT) began long ago in evolutionary terms with its recognition as a classical neurohypophyseal hormone important for lactation and uterine contraction. With the recent discovery of its local actions in the brain, its previously unappreciated diverse functions in regulating social behaviors and metabolic physiology are emerging. In light of metabolic control, OXT has been shown to induce feeding restriction and body weight lowering through acting on brain regulatory regions, in particular the hypothalamus. Studies from pharmacologic interventions and genetic manipulations demonstrated that OXT can play significant roles in affecting glucose metabolism as well as insulin secretion and lipolysis, many of those functions being regulated both centrally and peripherally. Also excitingly, recent therapeutic success was obtained in clinical endeavor showing that OXT nasal spray effectively induced weight loss and metabolic improvement in human patients with obesity, thus further indicating OXT as a tangible drug target for treating obesity and metabolic complications. In addition to the native form, OXT-derived analogues have been found effective in inducing body weight control and glucose balance. Altogether, all recent advances in the understanding of OXT and metabolic regulation has laid a promising foundation for the therapeutic strategy of developing innovative OXT peptidyl drugs for the treatment of obesity and related metabolic diseases

Obesity, a major risk factor for the development of type II diabetes, cardiovascular diseases, and cancer, is rising at an alarming rate worldwide. Obesity is caused by a chronic imbalance between energy expenditure and energy storage by adipose tissue. Adipogenesis is the process governing the formation and function of adipose tissue. This review article will discuss the most recent advances in understanding the regulation of adipogenesis, including adipose tissue lineage determination, the identity of the adipocyte progenitor cells, novel regulators controlling energy storage and expenditure and lastly the newly identified beige/brite cells.

As rates of obesity soar in the Unites States and around the world, cancer attributed to obesity has emerged as a major threat to public health. The link between obesity and cancer can be attributed in part to the state of chronic inflammation, which develops in obesity. Acetyl-CoA production and protein acetylation patterns are highly sensitive to metabolic state and are significantly altered in obesity. In this article, we explore the potential role of nutrient-sensitive lysine acetylation in regulating inflammatory processes in obesity-linked cancer.

Obesity and obesity-related complications are epidemic issues currently plaguing much of the developed world with increasing associated morbidity, mortality, and economic burden. In this brief review, we discuss emerging evidence and remaining questions regarding the possible role for mitochondrial sirtuin 3 as a therapeutic target for the treatment of obesity-related metabolic diseases.

Measures of general adiposity have limitations in the prediction of metabolic complications of obesity. Body fat compartments, such as abdominal visceral fat, interscapular fat, perivascular fat around the brachial artery, perivascular fat around the thoracic artery and liver fat content, correlate better with insulin resistance, glucose intolerance, diabetes and hypertension than body mass index. Finding the origin of specific fat compartments could help in the development of new therapeutic strategies.

The profound genetic determination of body fat distribution has been demonstrated in twin studies and complex segregation analyses. Genome-wide association studies delivered clear evidence for an association of specific genes or genetic regions with waist-to-hip ratio, waist circumference, visceral fat area, and pericardial fat determined by computed tomography. Many of these SNPs and genes also associate with metabolic end-points, such as insulin resistance and diabetes. Candidate gene studies also discovered polymorphisms that are suggested to be associated with markers of body fat distribution. Although most of the results of small studies are not replicated, the problem with hypothesis-free approaches is the low effect size of discovered variants and, in most cases, the lack of pathomechanistic explanations. Further studies using more sophisticated methods for the assessment of body fat distribution are needed to advance our knowledge in this field.

Airway remodeling is a crucial part of the pathogenesis of asthma. Epithelial-mediators may drive changes in other tissues, including the extracellular matrix, airway smooth muscle and the bronchial vascular bed. Several novel pharmacological therapies target goblet cell differentiation. Airway smooth muscle hyperplastic growth is mediated via the epidermal growth factor receptor via the cysLT receptor 1 but is also responsive to a variety of other pharmacological interventions. Anti-IL-5 treatment and prostaglandin E receptor agonists may reduce airway matrix protein deposition. Studies of vascular remodeling are lacking. There is a need for the development of inhibitors of remodeling that have acceptable toxicity and are validated in human subjects.

Despite its prevalence and cost to the healthcare system, the pathogenesis of asthma remains poorly understood. It is clear that asthma is a heterogeneous disease and recent approaches have attempted to define asthma subgroups based on inflammatory phenotypes. Characteristics of the cellular makeup of sputum, blood, bronchoalveolar lavage fluid, and endobronchial biopsies have been examined in asthmatic subjects, with a primary focus on eosinophils and neutrophils, and, more recently, mast cells. The inflammatory phenotypes identified to date include eosinophilic asthma, neutrophilic asthma, pauci-granulocytic asthma, and T helper 2-associated asthma. Defining these phenotypes has already led to more personalized and successful targeted therapies, with new developments on the horizon.

While asthma is an inflammatory disorder of the conducting airways with strong allergic overtones, the variable and often low clinical response to selective treatments that target the Th2 pathway have been disappointing. Beyond mild disease, asthma is a disorder of epithelial damage and aberrant repair with recapitulation of regenerative pathways that are prominent in foetal lung morphogenesis. This has led to the concept of activation of chronic asthma being maintained by persistent activation of the epithelial mesenchymal trophic unit by biologically active allergens, microorganisms and pollutants to drive inflammation in parallel with airway remodelling. Such mechanisms provide a basis for novel therapies directed towards increasing the lung's resistance to the inhaled environment and improving repair rather than concentrating on suppressing inflammation.

Asthma is a complex disorder of the airways that is characterized by T helper type 2 (Th2) inflammation. The pleiotrophic cytokine TSLP has emerged as an important player involved in orchestrating the inflammation seen in asthma and other atopic diseases. Early research elucidated the role of TSLP on CD4⁺ T cells, and recent work has revealed the impact of TSLP on multiple cell types. Furthermore, TSLP plays an important role in the sequential progression of atopic dermatitis to asthma, clarifying the key role of TSLP in the pathogenesis of asthma, a finding with therapeutic implications.