Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30–50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.

Elastic fibres are a major class of extracellular matrix fibres that are abundant in dynamic connective tissues such as arteries, lungs, skin and ligaments. Their structural role is to endow tissues with elastic recoil and resilience. They also act as an important adhesion template for cells, and they regulate growth factor availability. Mutations in major structural components of elastic fibres, especially elastin, fibrillins and fibulin-5, cause severe, often life-threatening, heritable connective tissue diseases such as Marfan syndrome, supravalvular aortic stenosis and cutis laxa. Elastic-fibre function is also frequently compromised in damaged or aged elastic tissues. The ability to regenerate or engineer elastic fibres and tissues remains a significant challenge, requiring improved understanding of the molecular and cellular basis of elastic-fibre biology and pathology, and ability to regulate the spatiotemporal expression and assembly of its molecular components.

DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

The unremitting emergence of multidrug-resistant bacterial pathogens highlights a matching need for new therapeutic options. For example, new carbapenemases such as KPC (class A Klebsiella pneumoniae) and NDM-1 (New Delhi metallo-β-lactamase 1) are surfacing, resulting in almost total resistance to β-lactam antibiotics. Furthermore, resistance is quickly disseminated, not only in the healthcare sector, but also within the community at large, because many resistance determinants are carried on mobile genetic elements readily shared among pathogens. The absence of new antibiotics has led to a growing reliance on older, more toxic drugs such as colistin, but resistance to these is already arising. One approach to combat this growing problem is the use of combination drug antibiotic adjuvant therapy, which potentiates the activity of antibiotics. Here, we review the current situation and discuss potential drug combinations that may increase the potency of antibiotics in the future. Adjuvant therapies include antibiotic combinations, synergy between antibiotics and nonantibiotics, inhibition of resistance and molecules that alter the physiology of antibiotic-insensitive cells, such as those in biofilms. We provide a rationale for these multicomponent strategies, highlighting current research and important considerations for their clinical use and pharmacological properties.

Polycystic ovarian syndrome (PCOS) is universally recognised as the commonest endocrinopathy of women. The definition and the aetiological hypotheses of PCOS are continuously evolving to accommodate expanding knowledge on the syndrome, which is now known to be more complex than purely a reproductive disorder. Increased androgen synthesis, disrupted folliculogenesis and insulin resistance lie at the pathophysiological core of PCOS. An intriguing concept involves the perpetuation of a vicious circle with endocrine/reproductive and metabolic components. An unfavourable metabolic environment may unmask genetic traits of ovarian dysfunction, and the unfolding endocrine derangement could further aggravate the metabolic disarray. This article reviews the molecular mechanisms known to underlie the ovarian and metabolic abnormalities characterising PCOS. The putative interdependence between reproductive and metabolic aspects of PCOS, and therapeutic implications for the management of PCOS, are also discussed.

The fluid mosaic model of the plasma membrane has evolved considerably since its original formulation 30 years ago. Membrane lipids do not form a homogeneous phase consisting of glycerophospholipids (GPLs) and cholesterol, but a mosaic of domains with unique biochemical compositions. Among these domains, those containing sphingolipids and cholesterol, referred to as membrane or lipid rafts, have received much attention in the past few years. Lipid rafts have unique physicochemical properties that direct their organisation into liquid-ordered phases floating in a liquid-crystalline ocean of GPLs. These domains are resistant to detergent solubilisation at 4°C and are destabilised by cholesterol- and sphingolipid-depleting agents. Lipid rafts have been morphologically characterised as small membrane patches that are tens of nanometres in diameter. Cellular and/or exogenous proteins that interact with lipid rafts can use them as transport shuttles on the cell surface. Thus, rafts act as molecular sorting machines capable of co-ordinating the spatiotemporal organisation of signal transduction pathways within selected areas (‘signalosomes’) of the plasma membrane. In addition, rafts serve as a portal of entry for various pathogens and toxins, such as human immunodeficiency virus 1 (HIV-1). In the case of HIV-1, raft microdomains mediate the lateral assemblies and the conformational changes required for fusion of HIV-1 with the host cell. Lipid rafts are also preferential sites of formation for pathological forms of the prion protein (PrPSc) and of the β-amyloid peptide associated with Alzheimer's disease. The possibility of modulating raft homeostasis, using statins and synthetic sphingolipid analogues, offers new approaches for therapeutic interventions in raft-associated diseases.

The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi are the causative agents of African trypanosomiasis and Chagas disease, respectively. These are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. Treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. Here, we review the properties of these drugs and describe new findings on their modes of action and the mechanisms by which resistance can arise. We further outline how a greater understanding of parasite biology is being exploited in the search for novel chemotherapeutic agents. This effort is being facilitated by new research networks that involve academic and biotechnology/pharmaceutical organisations, supported by public–private partnerships, and are bringing a new dynamism and purpose to the search for trypanocidal agents.

Androgenetic alopecia occurs in men and women, and is characterised by the loss of hair from the scalp in a defined pattern. Determining factors appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. The prevalence of this condition is high (up to 50% of white males are affected by 50 years of age) and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Knowledge of the pathogenesis of androgenetic alopecia has increased markedly in recent years. Pre-programmed follicles on the scalp undergo a transformation from long growth (anagen) and short rest (telogen) cycles, to long rest and short growth cycles. This process is coupled with progressive miniaturisation of the follicle. These changes are androgen dependent, and require the inheritance of several genes. To date, only one of these genes, which encodes the androgen receptor (AR), has been identified. Of the many treatments available for androgenetic alopecia, only two (finasteride and minoxidil) have been scientifically shown to be useful in the treatment of hair loss. However, these therapies are variable in their effectiveness. Discovery of the involvement of the AR gene, and the identification of other genes contributing to the condition, might lead to the development of new and more effective therapies that target the condition at a more fundamental level.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a zinc-finger DNA-binding enzyme that is activated by binding to DNA breaks. Poly(ADP-ribosyl)ation of nuclear proteins by PARP-1 converts DNA damage into intracellular signals that activate either DNA repair by the base-excision pathway or cell death. A family of 18 PARPs has been identified, but only the most abundant, PARP-1 and PARP-2, which are both nuclear enzymes, are activated by DNA damage. PARP inhibitors of ever-increasing potency have been developed in the 40 years since the discovery of PARP-1, both as tools for the investigation of PARP-1 function and as potential modulators of DNA-repair-mediated resistance to cytotoxic therapy. Owing to the high level of homology between the catalytic domains of PARP-1 and PARP-2, the inhibitors probably affect both enzymes. Convincing biochemical evidence, which has been corroborated by genetic manipulation of PARP-1 activity, shows that PARP inhibition is associated with increased sensitivity to DNA-alkylating agents, topoisomerase I poisons and ionising radiation. Novel PARP inhibitors of sufficient potency and suitable pharmacokinetic properties to allow evaluation in animal models have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation; indeed, the combination with temozolomide resulted in complete tumour regression in two independent studies. The combination of a PARP inhibitor and temozolomide is currently undergoing clinical evaluation for the first time.

Elastic fibres are insoluble components of the extracellular matrix of dynamic connective tissues such as skin, arteries, lungs and ligaments. They are laid down during development, and comprise a cross-linked elastin core within a template of fibrillin-based microfibrils. Their function is to endow tissues with the property of elastic recoil, and they also regulate the bioavailability of transforming growth factor β. Severe heritable elastic fibre diseases are caused by mutations in elastic fibre components; for example, mutations in elastin cause supravalvular aortic stenosis and autosomal dominant cutis laxa, mutations in fibrillin-1 cause Marfan syndrome and Weill–Marchesani syndrome, and mutations in fibulins-4 and -5 cause autosomal recessive cutis laxa. Acquired elastic fibre defects include dermal elastosis, whereas inflammatory damage to fibres contributes to pathologies such as pulmonary emphysema and vascular disease. This review outlines the latest understanding of the composition and assembly of elastic fibres, and describes elastic fibre diseases and current therapeutic approaches.

The central component of hypoxia sensing in the cell is the hypoxia-inducible factor (HIF) transcriptional complex. HIF activity is deregulated in many human cancers, especially those that are highly hypoxic. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Overexpression of HIF-α, the regulatory subunit of HIF, is associated with increased vascular density, severity of tumour grade, treatment failure and a poor prognostic outcome with conventional therapies. Therefore HIF is an attractive, although challenging, therapeutic target, and several different strategies have been developed to target HIF directly or indirectly in recent years. This review outlines the preclinical and clinical advances in this arena and discusses which cancers may benefit from HIF-targeted therapy.

Wound healing is a complex process that we have only recently begun to understand. Central to wound repair is transforming growth factor β (TGF-β), a cytokine secreted by several different cell types involved in healing. TGF-β has diverse effects, depending upon the tissue studied. This review focuses on healing in skin, particularly the phases of cutaneous wound repair and the role of TGF-β in normal and impaired wound-healing models. It also explores TGF-β activity in scarless foetal wound healing. Knowledge of TGF-β function in scarless repair is critical to improving healing in clinical scenarios, such as diabetic wounds and hypertrophic scars.

During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, which occurs in hypertrophic scars or tissue fibrosis, results in a loss of function. Many reviews outline the cellular and molecular features of myofibroblasts and their roles in a variety of diseases. This review focuses on the origins of myofibroblasts and the factors that control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts originate mostly from tissue-resident fibroblasts, and also from epithelial and endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, which promotes their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT–β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

The GATA family of transcription factors consists of six proteins (GATA1-6) which are involved in a variety of physiological and pathological processes. GATA1/2/3 are required for differentiation of mesoderm and ectoderm-derived tissues, including the haematopoietic and central nervous system. GATA4/5/6 are implicated in development and differentiation of endoderm- and mesoderm-derived tissues such as induction of differentiation of embryonic stem cells, cardiovascular embryogenesis and guidance of epithelial cell differentiation in the adult.

Rubinstein–Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100 000 newborns. Mutations in two genes – CREBBP and EP300 – have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein–Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein–Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.

Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood–brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.

Autophagy is a catabolic membrane-trafficking process that leads to sequestration and degradation of intracellular material within lysosomes. It is executed at basal levels in every cell and promotes cellular homeostasis by regulating organelle and protein turnover. In response to various forms of cellular stress, however, the levels and cargoes of autophagy can be modulated. In nutrient-deprived states, for example, autophagy can be activated to degrade cargoes for cell-autonomous energy production to promote cell survival. In other contexts, in contrast, autophagy has been shown to contribute to cell death. Given these dual effects in regulating cell viability, it is no surprise that autophagy has implications in both the genesis and treatment of malignant disease. In this review, we provide a comprehensive appraisal of the way in which oncogenes and tumour suppressor genes regulate autophagy. In addition, we address the current evidence from human cancer and animal models that has aided our understanding of the role of autophagy in tumour progression. Finally, the potential for targeting autophagy therapeutically is discussed in light of the functions of autophagy at different stages of tumour progression and in normal tissues.

Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarise, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins, and survey strategies and progress towards developing therapeutics aimed at the APOBEC3–Vif axis.

Over the past two decades, a convergence of basic and clinical evidence has established the neuropeptide calcitonin-gene-related peptide (CGRP) as a key player in migraine. Although CGRP is a recognised neuromodulator of nociception, its mechanism of action in migraine remains elusive. In this review, we present evidence that led us to propose that CGRP is well poised to enhance neurotransmission in migraine by both peripheral and central mechanisms. In the periphery, it is thought that local release of CGRP from the nerve endings of meningeal nociceptors following their initial activation by cortical spreading depression is critical for the induction of vasodilation, plasma protein extravasation, neurogenic inflammation and the consequential sensitisation of meningeal nociceptors. Mechanistically, we propose that CGRP release can give rise to a positive-feedback loop involved in localised increased synthesis and release of CGRP from neurons and a CGRP-like peptide called procalcitonin from trigeminal ganglion glia. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator.

Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies.