Common to all forms of chronic kidney disease is the progressive scarring of the tubulo-interstitial space, associated with the acquisition and accumulation of activated myofibroblasts. Many of these myofibroblasts are generated when tubular epithelial cells progressively lose their epithelial characteristics (cell–cell contact, microvilli, tight-junction proteins, apical–basal polarity) and acquire features of a mesenchymal lineage, including stress fibres, filopodia and augmented matrix synthesis. This process, known as epithelial to mesenchymal transition (EMT), plays an important role in progressive kidney disease. For EMT to occur in tubular cells, the transcriptional activation (and derepression) of genes required to sustain mesenchymal-type structures and functions (e.g. vimentin, α-smooth muscle actin) must occur alongside repression (or deactivation) of genes that act to maintain the epithelial phenotype (e.g. E-cadherin, bone morphogenic protein 7). Several factors have been suggested as potential initiators of EMT. With a few key exceptions, these triggers require the induction of transforming growth factor β (TGF-β) and downstream mediators, including SMADs, CTGF, ILK and SNAI1. Activation of TGF-β receptors is also able to stimulate a range of additional pathways (so-called non-SMAD activation), including RhoA, mitogen-activated protein kinase and phosphoinositide 3-kinase signalling cascades, that also contribute to EMT and renal fibrogenesis. This review examines in detail the molecular mediators of EMT in tubular cells and its potential role as a long-lasting mediator of metabolic stress.

Pyroptosis is a recently identified mechanism of programmed cell death related to Caspase-1 that triggers a series of inflammatory reactions by releasing several proinflammatory factors such as IL-1β and IL-18. The process is characterised by the rupture of cell membranes and the release of cell contents through the mediation of gasdermin (GSDM) proteins. GSDMD is an important member of the GSDM family and plays a critical role in the two pathways of pyroptosis. Diabetic nephropathy (DN) is a microvascular complication of diabetes and a major cause of end-stage renal disease. Recently, it was revealed that GSDMD-mediated pyroptosis plays an important role in the occurrence and development of DN. In this review, we focus on two types of kidney cells, tubular epithelial cells and renal podocytes, to illustrate the mechanism of pyroptosis in DN and provide new ideas for the prevention, early diagnosis and molecular therapy of DN.

The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. Complement is involved in host defence by triggering the generation of a membranolytic complex (the C5b-9 complex) at the surface of the pathogen. Complement fragments (opsonins; C1q, C3b and iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host. Complement is of special importance in the brain, where entrance of elements of the adaptive immune system is restricted by a blood–brain barrier. There is now compelling evidence that complement is produced locally in response to an infectious challenge. Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's and Pick's diseases, and the cytolytic/cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g. amyloid fibrils) and apoptotic cells, as well as in promoting tissue repair through the anti-inflammatory activities of C3a. Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.

Although the complete picture for alopecia areata (AA) pathogenesis has yet to be determined, recent research has made much progress in our understanding of the disease mechanism. Numerous circumstantial evidence supports the notion that AA is fundamentally a disease mediated by inflammatory cells and may be autoimmune in nature. Recent research has shown the hair-loss phenotype is precipitated predominantly by CD8+ lymphocytes, but the disease mechanism is driven by CD4+ lymphocytes. Although genetic susceptibility is a key contributor to disease development, disease onset and phenotypic presentation are probably modified by complex environmental interplay. On the basis of our current understanding of AA disease pathogenesis, several experimental and theoretical therapeutic approaches might be possible. However, the pathogenetic disease mechanism is particularly robust and the development of a cure for AA will be a significant challenge.

Adipose-derived stem cells (ASCs) are considered a great alternative source of mesenchymal stem cells (MSCs). Unlike bone marrow stem cells (BMSCs), ASCs can be retrieved in high numbers from lipoaspirate, a by-product of liposuction procedures. Given that ASCs represent an easily accessible and abundant source of multipotent cells, ASCs have garnered attention and curiosity from both scientific and clinical communities for their potential in clinical applications. Furthermore, their unique immunobiology and secretome are attractive therapeutic properties. A decade since the discovery of a stem cell reservoir residing within adipose tissue, ASC-based clinical trials have grown over the years around the world along with assessments made on their safety and efficacy. With the progress of ASCs into clinical applications, the aim towards producing clinical-grade ASCs becomes increasingly important. Several countries have recognised the growing industry of cell therapies and have developed regulatory frameworks to assure their safety. With more research efforts made to understand their effects in both scientific and clinical settings, ASCs hold great promise as a future therapeutic strategy in treating a wide variety of diseases. Therefore, this review seeks to highlight the clinical applicability of ASCs as well as their progress in clinical trials across various medical disciplines.

Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications.

Breast cancer is a heterogeneous disease and classification is important for clinical management. At least five subtypes can be identified based on unique gene expression patterns; this subtype classification is distinct from the histopathological classification. The transcription factor network(s) required for the specific gene expression signature in each of these subtypes is currently being elucidated. The transcription factor network composed of the oestrogen (estrogen) receptor α (ERα), FOXA1 and GATA3 may control the gene expression pattern in luminal subtype A breast cancers. Breast cancers that are dependent on this network correspond to well-differentiated and hormone-therapy-responsive tumours with good prognosis. In this review, we discuss the interplay between these transcription factors with a particular emphasis on FOXA1 structure and function, and its ability to control ERα function. Additionally, we discuss modulators of FOXA1 function, ERα–FOXA1–GATA3 downstream targets, and potential therapeutic agents that may increase differentiation through FOXA1.

Spinal cord injury is one of the most devastating conditions that affects the central nervous system. It can lead to permanent disability and there are around two million people affected worldwide. After injury, accumulation of myelin debris and formation of an inhibitory glial scar at the site of injury leads to a physical and chemical barrier that blocks axonal growth and regeneration. The mammalian central nervous system thus has a limited intrinsic ability to repair itself after injury. To improve axonal outgrowth and promote functional recovery, it is essential to identify the various intrinsic and extrinsic factors controlling regeneration and navigation of axons within the inhibitory environment of the central nervous system. Recent advances in spinal cord research have opened new avenues for the exploration of potential targets for repairing the cord and improving functional recovery after trauma. Here, we discuss some of the important key molecules that could be harnessed for repairing spinal cord injury.

Retroviruses, such as human immunodeficiency virus type 1 (HIV-1), are plus-sense RNA viruses that require reverse transcription and then DNA integration to establish a chromosomal provirus as an obligate replication intermediate. The viral enzyme reverse transcriptase synthesises linear double-stranded cDNA, which is the template for the viral enzyme integrase. Integrase catalyses two separate chemical reactions: an initial 3′ processing of the nascent cDNA ends, which is followed in the cell nucleus by their covalent attachment to the 5′ phosphates of a double-stranded staggered cut in chromosomal DNA. As integrase activity is essential for productive retroviral infection, there is intense interest in developing small-molecule inhibitors of the HIV-1 enzyme to increase the breadth of the antiviral arsenal used to fight HIV/AIDS. Purified integrase protein displays the 3′ processing and DNA-strand-transfer activities essential for cDNA integration in integration assays in vitro, but numerous studies indicate that cellular proteins play important roles during integration in infected cells. This review highlights the molecular mechanisms behind HIV-1 integration, focusing on recent insights into functions of human cellular cofactors. The progress towards developing integrase inhibitors for their use in the clinic is also reviewed.

MicroRNAs (miRNAs) are a family of endogenous small noncoding RNA molecules, of 19–28 nucleotides in length. In humans, up to 3% of all genes are estimated to encode these evolutionarily conserved sequences. miRNAs are thought to control expression of thousands of target mRNAs. Mammalian miRNAs generally negatively regulate gene expression by repressing translation, possibly through effects on mRNA stability and compartmentalisation, and/or the translation process itself. An extensive range of in silico and experimental techniques have been applied to our understanding of the occurrence and functional relevance of such sequences, and antisense technologies have been successfully used to control miRNA expression in vitro and in vivo. Interestingly, miRNAs have been identified in both normal and pathological conditions, including differentiation and development, metabolism, proliferation, cell death, viral infection and cancer. Of specific relevance and excitement to the area of diabetes research, miRNA regulation has been implicated in insulin secretion from pancreatic β-cells, diabetic heart conditions and nephropathy. Further analyses of miRNAs in vitro and in vivo will, undoubtedly, enable us determine their potential to be exploited as therapeutic targets in diabetes.

Fertilisation is an orchestrated, stepwise process during which the participating male and female gametes undergo irreversible changes, losing some of their structural components while contributing others to the resultant zygote. Following sperm penetration through the egg coat, the sperm plasma membrane fuses with its oocyte counterpart, the oolemma. At least two plasma membrane proteins essential for sperm–oolemma fusion – IZUMO and CD9 on the male and female gametes, respectively – have been identified recently by classical cell biology approaches and confirmed by gene deletion. Oolemma-associated tetraspanin CD81, closely related to CD9, also appears to have an essential role in fusion. Additional proteins that may have nonessential yet still facilitating roles in sperm–oolemma adhesion and fusion include oolemma-anchored integrins and oocyte-expressed retroviral envelope proteins, sperm disintegrins, and sperm-borne proteins of epididymal origin such as CRISP1 and CRISP2. This review discusses these components of the gamete fusion mechanism within the framework of gamete structure, membrane biology, cell signalling and cytoskeletal dynamics, and revisits the topic of antipolyspermy defence at the oolemma level. Harnessing the mechanisms of sperm–egg fusion is of importance to animal biotechnology and to human assisted fertilisation, wherein male patients with reduced sperm fusibility have been identified.

Arboviruses are pathogens that widely affect the health of people in different communities around the world. Recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. The arbovirus infection and replication processes are complex, and many factors are involved in their regulation. Apoptosis, autophagy and the unfolded protein response (UPR) are three mechanisms that are involved in pathogenesis of many viruses. In this review, we focus on the importance of these pathways in the arbovirus replication and infection processes. We provide a brief introduction on how apoptosis, autophagy and the UPR are initiated and regulated, and then discuss the involvement of these pathways in regulation of arbovirus pathogenesis.

The primary hyperoxalurias type 1 (PH1) and type 2 (PH2) are autosomal recessive calcium oxalate kidney stone diseases caused by deficiencies of the metabolic enzymes alanine:glyoxylate aminotransferase (AGT) and glyoxylate/hydroxypyruvate reductase (GR/HPR), respectively. Over 50 mutations have been identified in the AGXT gene (encoding AGT) in PH1, associated with a wide variety of effects on AGT, including loss of catalytic activity, aggregation, accelerated degradation, and peroxisome-to-mitochondrion mistargeting. Some of these mutations segregate and interact synergistically with a common polymorphism. Over a dozen mutations have been found in the GRHPR gene (encoding GR/HPR) in PH2, all associated with complete loss of glyoxylate reductase enzyme activity and immunoreactive protein. The crystal structure of human AGT, but not human GR/HPR, has been solved, allowing the effects of many of the mutations in PH1 to be rationalised in structural terms. Detailed analysis of the molecular aetiology of PH1 and PH2 has led to significant improvements in all aspects of their clinical management. Enzyme replacement therapy by liver transplantation can provide a metabolic cure for PH1, but it has yet to be tried for PH2. New treatments that aim to counter the effects of specific mutations on the properties of the enzymes could be feasible in the not-too-distant future.

Autoimmune disease manifests in numerous forms, but as a disease group is relatively common in the population. It is complex in aetiology, with genetic and environmental determinants. The involvement of gene variants in autoimmune disease is well established, and evidence for significant involvement of the environment in various disease forms is growing. These factors may act independently, or they may interact, with the effect of one factor influenced by the presence of another. Identifying combinations of genetic and environmental factors that interact in autoimmune disease has the capacity to more fully explain disease risk profile, and to uncover underlying molecular mechanisms contributing to disease pathogenesis. In turn, such knowledge is likely to contribute significantly to the development of personalised medicine, and targeted preventative approaches. In this review, we consider the current evidence for gene–environment (G–E) interaction in autoimmune disease. Large-scale G–E interaction research efforts, while well-justified, face significant practical and methodological challenges. However, it is clear from the evidence that has already been generated that knowledge on how genes and environment interact at a biological level will be crucial in fully understanding the processes that manifest as autoimmunity.

Salmonella enterica causes a range of life-threatening diseases in humans and animals worldwide. Current treatments for S. enterica infections are not sufficiently effective, and there is a need to develop new vaccines and therapeutics. An understanding of how S. enterica spreads in tissues has very important implications for targeting bacteria with vaccine-induced immune responses and antimicrobial drugs. Development of new control strategies would benefit from a more sophisticated evaluation of bacterial location, spatiotemporal patterns of spread and distribution in the tissues, and sites of microbial persistence. We review here recent studies of S. enterica serovar Typhimurium (S. Typhimurium) infections in mice, an established model of systemic typhoid fever in humans, which suggest that continuous bacterial spread to new infection foci and host phagocytes is an essential trait in the virulence of S. enterica during systemic infections. We further highlight how infections within host tissues are truly heterogeneous processes despite the fact that they are caused by the expansion of a genetically homogeneous microbial population. We conclude by discussing how understanding the within-host quantitative, spatial and temporal dynamics of S. enterica infections might aid the development of novel targeted preventative measures and drug regimens.

The bioactive lipids lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), the enzymes that generate and degrade them, and the receptors that receive their signals are all potential therapeutic targets in cancer. LPA and S1P signalling pathways can modulate a range of cellular processes that contribute to tumourigenesis, such as proliferation and motility, and components of the signalling pathways often show aberrant expression and altered activity upon malignant transformation. This article reviews LPA- and S1P-mediated activities that might contribute to the aetiology of cancer, and examines the potential of the many antagonists that have been developed to inhibit LPA and S1P signalling pathways. In addition, the outcomes of various clinical trials using LPA- and S1P-associated targets in cancer and other diseases are described, and future directions are discussed.

Tumour hypoxia stems from impaired oxygen delivery as a result of a disorganised tumour vasculature and inadequate blood supply. Hypoxic tumours are highly resistant to chemotherapy and radiation therapy and correlate with a poor patient prognosis. Hypoxia is a powerful stimulus for the expression of genes involved in cell survival and angiogenesis. A key factor in this process is hypoxia-inducible factor (HIF), which regulates transcription of hypoxia-activated genes. Efforts are currently under way to develop targeted cancer therapeutics to hypoxia-activated pathways, and in particular to the transcription factor HIF.

Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

Humans and other vertebrates exhibit left–right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, including situs inversus and heterotaxy. Situs inversus is complete mirror-imaged arrangement of the internal organs along LR axis, whereas heterotaxy is abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved in situs inversus and heterotaxy have been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders.

Preterm birth (PTB) complicates more than 12% of all deliveries. Despite significant research, the aetiology of most cases of PTB remains elusive. Two major antecedents of PTB, intra-amniotic infection and decidual haemorrhage (abruption), can exhibit dissimilar demographic and genetic predispositions, despite sharing common molecular and cellular pathways. The use of high-throughput, high-dimensional technologies reveals substantial crosstalk between the coagulation and inflammation pathways. Tissue factor, thrombin and cytokines are key mediators of this crosstalk. Abruptions are associated with excess thrombin generated from decidual-cell-expressed tissue factor. Although thrombin is a primary mediator of the coagulation cascade, it can also promote inflammation-associated PTB by enhancing expression of matrix metalloproteinase and neutrophil-chemoattracting and -activating chemokines. Here, we provide novel insights into the molecular mechanisms and pathways leading to PTB in the setting of placental abruption.