Handbook of experimental pharmacology最新文献

The chapter provides a brief overview on current methodologies for the assembly of complex oligosaccharides by chemical synthesis. Following an introductory section describing the major factors and variables involved in glycosylation reactions, select examples for advanced approaches towards mammalian and bacterial glycans are discussed illustrating recent progress in the field of glycochemistry.

Metabolic syndrome (MetS) is a prevalent health condition that requires significant attention and intervention due to its multifaceted nature. It encompasses a variety of ailments such as diabetes mellitus, hypertension, obesity, and dyslipidemia. Despite extensive research, the underlying pathophysiology of MetS is not entirely understood, and current synthetic drugs used to treat it have adverse effects and can be expensive. Therefore, natural products are being investigated as a potential alternative treatment for MetS. This chapter provides an overview of studies on natural products as a treatment for MetS. The available evidence suggests that bioactive phytochemicals and herbal medicines, such as curcumin, resveratrol, Nigella sativa, Hibiscus sabdariffa, and Theobroma cacao, have the potential to treat MetS effectively. Furthermore, natural products can be explored as a novel drug discovery approach for MetS. However, it is imperative to conduct well-designed randomized controlled trials with large sample sizes to confirm these findings. Based on our review, we conclude that natural products could be a promising alternative for treating MetS. Further research is warranted to explore this potential fully. The use of natural products for MetS treatment could reduce the reliance on synthetic drugs, many of which have harmful side effects and are costly. The development of natural products as a treatment for MetS could have significant implications for public health, and we encourage further research in this area.

Glycosaminoglycans (GAGs), linear anionic periodic polysaccharides, play pivotal roles in various biologically relevant processes within the extracellular matrix (ECM). These processes encompass cell development, proliferation, signaling, ECM assembly, coagulation, and angiogenesis. GAGs perform their functions through their interactions with specific protein partners, rendering them attractive targets for regenerative medicine and drug design. However, the molecular mechanisms governing protein-GAG interactions remain unclear. Classical structure determination techniques face significant challenges when dealing with protein-GAG complexes. This is due to GAGs' unique properties, including their extensive length, flexibility, periodicity, symmetry, multipose binding, and the high heterogeneity of their sulfation patterns constituting the "sulfation code." Consequently, only a limited number of experimental protein-GAG structures have been elucidated. Hence, theoretical approaches are particularly promising in deciphering the code for understanding the structure-function relationship of these complex molecules. In this chapter, we focus on the particularities, challenges, and advances of computational methods such as molecular docking, molecular dynamics, and free-energy calculations when applied to GAG-containing systems. These computational approaches offer valuable insights into the enigmatic world of protein-GAG interactions, paving the way for their enhanced understanding and potential therapeutic applications.

Despite an increasing number of clinical trials, cancer is one of the leading causes of death worldwide in the past decade. Among all complex diseases, clinical trials in oncology have among the lowest success rates, in part due to the high intra- and inter-tumoral heterogeneity. There are more than a thousand cancer drugs and treatment combinations being investigated in ongoing clinical trials for various cancer subtypes, germline mutations, metastasis, etc. Particularly, treatments relying on the (re)activation of the immune system have become increasingly present in the clinical trial pipeline. However, the complexities of the immune response and cancer-immune interactions pose a challenge to the development of these therapies. Quantitative systems pharmacology (QSP), as a computational approach to predict tumor response to treatments of interest, can be used to conduct in silico clinical trials with virtual patients (and emergent use of digital twins) in place of real patients, thus lowering the time and cost of clinical trials. In line with improved mechanistic understanding of the human immune system and promising results from recent cancer immunotherapy, QSP models can play critical roles in model-informed drug development in immuno-oncology. In this chapter, we discuss how QSP models were designed to serve different study objectives, including hypothesis testing, dose optimization, and efficacy prediction, via case studies in immuno-oncology.

Maintaining good vascular health is a major component in healthy ageing as it reduces the risk of cardiovascular diseases. Endothelial dysfunction, in particular, is a key mechanism in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. Recently, endothelial senescence has emerged as a pivotal early event in age-related endothelial dysfunction. Endothelial function is characterized by an imbalance between the endothelial formation of vasoprotective mechanisms, including the formation of nitric oxide (NO) and endothelium-dependent hyperpolarization responses, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidases and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that natural products, in particular several polyphenol-rich foods, can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. In addition, some can even exert beneficial effects on endothelial senescence. Moreover, some of these products have been associated with the prevention and/or improvement of established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. Therefore, intake of certain natural products, such as dietary and plant-derived polyphenol-rich products, appears to be an attractive approach for a healthy vascular system in ageing.

Mass spectrometry-based techniques have emerged as a gamechanger for the analysis of carbohydrates. Here, we summarize state-of-the-art glycan analysis in vacuo, demonstrating how mass spectrometry, tandem mass spectrometry, ion mobility spectrometry, and gas-phase infrared spectroscopy, supported by chromatography methods and computational modelling, facilitate the structural characterization of isolated glycans and the analysis of the entire glycome. After an introduction to glycans and techniques, the sugar classes of N-glycans, O-glycans, human milk oligosaccharides, and glycosaminoglycans will be discussed in detail, before the chapter ends with an outlook on the future of mass spectrometry-based glycan analysis.

Structural alterations of the glycan chains attached to glycoproteins and glycolipids are present in all types of malignomas investigated to date, including adenocarcinomas, sarcomas and haematological malignancies. They occur in humans as well as in animals including experimental models of malignancy, regardless of the type, cause, or stage of the tumour. The biochemical and genomic characterization of the enzymatic machineries involved in glycan biosynthesis in cancer cells shows that tumour-associated glycosylation changes are a critical part of tumour initiation and progression. Experimental studies and epidemiological findings give clear evidence that tumour-associated glycans bear functional significance in the invasive and metastatic growth of malignancies, for immunological tumour defence and, hence, influence the clinical outcome and the prognosis of cancer patients. Tumour-associated glycan changes are, moreover, targets for new pharmacological and immunological therapy methods and serve as important clinical biomarkers for diagnosis, particularly for monitoring disease progression and therapeutic efficacy. This chapter provides an overview of the major types of changes of glycosylation, genetic and biochemical mechanisms contributing to cancer-associated glycosylation, functional consequences for tumour growth and the clinical significance in cancer diagnosis, monitoring and treatment.

Proteins and peptides are highly desirable as therapeutic agents, being highly potent and specific. However, there are myriad challenges with processing them into patient-friendly formulations: they are often unstable and have a tendency to aggregate or degrade upon storage. As a result, the vast majority of protein actives are delivered parenterally as solutions, which has a number of disadvantages in terms of cost, accessibility, and patient experience. Much work has been undertaken to develop new delivery systems for biologics, but to date this has led to relatively few products on the market. In this chapter, we review the challenges faced when developing biologic formulations, discuss the technologies that have been explored to try to overcome these, and consider the different delivery routes that can be applied. We further present an overview of the currently marketed products and assess the likely direction of travel in the next decade.

The mineralocorticoid aldosterone is produced in the zona glomerulosa of the adrenal cortex. Its synthesis is regulated by the serum concentrations of the peptide hormone angiotensin II and potassium. The primary role of aldosterone is to control blood volume and electrolytes. The autonomous production of aldosterone (primary aldosteronism, PA) is considered the most frequent cause of secondary hypertension. Aldosterone-producing adenomas and (micro-)nodules are frequent causes of PA and often carry somatic mutations in ion channels and transporters. Rare familial forms of PA are due to germline mutations. Both somatic and germline mutations in the chloride channel gene CLCN2, encoding ClC-2, have been identified in PA. Clinical findings and results from cell culture and animal models have advanced our knowledge about the role of anions in PA. The zona glomerulosa of the adrenal gland has now been firmly established as a tissue in which anions play a significant role for signaling. In this overview, we aim to summarize the current knowledge and highlight novel concepts as well as open questions.

Distress, or negative stress, is known to considerably increase the incidence of several diseases, including cancer. There is indeed evidence from pre-clinical models that distress causes a catecholaminergic overdrive that, mainly through the activation of β-adrenoceptors (β-ARs), results in cancer cell growth and cancer progression. In addition, clinical studies have evidenced a role of negative stress in cancer progression. Moreover, plenty of data demonstrates that β-blockers have positive effects in reducing the pro-tumorigenic activity of catecholamines, correlating with better outcomes in some type of cancers as evidenced by several clinical trials. Among β-ARs, β2-AR seems to be the main β-AR subtype involved in tumor development and progression. However, there are data indicating that also β1-AR and β3-AR may be involved in certain tumors. In this chapter, we will review current knowledge on the role of the three β-AR isoforms in carcinogenesis as well as in cancer growth and progression, with particular emphasis on recent studies that are opening new avenues in the use of β-ARs as therapeutic targets in treating tumors.