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 translation initiation factor eIF4E mediates a rate-limiting process that drives selective translation of many oncongenic proteins such as cyclin D1, survivin and VEGF, thereby contributing to tumour growth, metastasis and therapy resistance. As an essential regulatory hub in cancer signalling network, many oncogenic signalling pathways appear to converge on eIF4E. Therefore, targeting eIF4E-mediated cap-dependent translation is considered a promising anticancer strategy. This paper reviews the strategies that can be used to target eIF4E, highlighting agents that target eIF4E activity at each distinct level.

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.

miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3′UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrPC), termed PrPTSE, are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

Cardiovascular diseases are the leading cause of death in developed countries. The aetiology is currently multifactorial, thus making them very difficult to prevent. Preclinical models of atherothrombotic diseases, including vulnerable plaque-associated complications, are now providing significant insights into pathologies like atherosclerosis, and in combination with the most recent advances in new non-invasive imaging technologies, they have become essential tools to evaluate new therapeutic strategies, with which can forecast and prevent plaque rupture. Positron emission tomography (PET)/computed tomography imaging is currently used for plaque visualisation in clinical and pre-clinical cardiovascular research, albeit with significant limitations. However, the combination of PET and magnetic resonance imaging (MRI) technologies is still the best option available today, as combined PET/MRI scans provide simultaneous data acquisition together with high quality anatomical information, sensitivity and lower radiation exposure for the patient. The coming years may represent a new era for the implementation of PET/MRI in clinical practice, but first, clinically efficient attenuation correction algorithms and research towards multimodal reagents and safety issues should be validated at the preclinical level.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a form of muscular dystrophy caused by mutations in calpain 3 (CAPN3). Several studies have implicated Ca2+ dysregulation as an underlying event in several muscular dystrophies, including LGMD2A. In this study we used mouse and human myotube cultures, and muscle biopsies in order to determine whether dysfunction of sarco/endoplasmatic Ca2+-ATPase (SERCA) is involved in the pathology of this disease. In CAPN3-deficient myotubes, we found decreased levels of SERCA 1 and 2 proteins, while mRNA levels remained comparable with control myotubes. Also, we found a significant reduction in SERCA function that resulted in impairment of Ca2+ homeostasis, and elevated basal intracellular [Ca2+] in human myotubes. Furthermore, small Ankyrin 1 (sAnk1), a SERCA1-binding protein that is involved in sarcoplasmic reticulum integrity, was also diminished in CAPN3-deficient fibres. Interestingly, SERCA2 protein was patently reduced in muscles from LGMD2A patients, while it was normally expressed in other forms of muscular dystrophy. Thus, analysis of SERCA2 expression may prove useful for diagnostic purposes as a potential indicator of CAPN3 deficiency in muscle biopsies. Altogether, our results indicate that CAPN3 deficiency leads to degradation of SERCA proteins and Ca2+ dysregulation in the skeletal muscle. While further studies are needed in order to elucidate the specific contribution of SERCA towards muscle degeneration in LGMD2A, this study constitutes a reasonable foundation for the development of therapeutic approaches targeting SERCA1, SERCA2 or sAnk1.

Trimethylamine (TMA) is a tertiary amine with a characteristic fishy odour. It is synthesised from dietary constituents, including choline, L-carnitine, betaine and lecithin by the action of microbial enzymes during both healthy and diseased conditions in humans. Trimethylaminuria (TMAU) is a disease typified by its association with the characteristic fishy odour because of decreased TMA metabolism and excessive TMA excretion. Besides TMAU, a number of other diseases are associated with abnormal levels of TMA, including renal disorders, cancer, obesity, diabetes, cardiovascular diseases and neuropsychiatric disorders. Aside from its role in pathobiology, TMA is a precursor of trimethylamine-N-oxide that has been associated with an increased risk of athero-thrombogenesis. Additionally, TMA is a major air pollutant originating from vehicular exhaust, food waste and animal husbandry industry. The adverse effects of TMA need to be monitored given its ubiquitous presence in air and easy absorption through human skin. In this review, we highlight multifaceted attributes of TMA with an emphasis on its physiological, pathological and environmental impacts. We propose a clinical surveillance of human TMA levels that can fully assess its role as a potential marker of microbial dysbiosis-based diseases.

The human follicular fluid (HFF) contains molecules and proteins that may affect follicle growth, oocyte maturation and competence acquiring. Despite the numerous studies, an integrated broad overview on biomolecular and patho/physiological processes that are proved or supposed to take place in HFF during folliculogenesis and oocyte development is still missing. In this review we report, for the first time, all the proteins unambiguously detected in HFF and, applying DAVID (Database for Annotation, Visualization and Integrated Discovery) and MetaCore bioinformatic resources, we shed new lights on their functional correlation, delineating protein patterns and pathways with reasonable potentialities for oocyte quality estimation in in vitro fertilisation (IVF) programs. Performing a rigorous PubMed search, we redacted a list of 617 unique proteins unambiguously-annotated as HFF components. Their functional processing suggested the occurrence in HFF of a tight and highly dynamic functional-network, which is balanced by specific effectors, primarily involved in extracellular matrix degradation and remodelling, inflammation and coagulation. Metalloproteinases, thrombin and vitamin-D-receptor/retinoid-X-receptor-alpha resulted as the main key factors in the nets and their differential activity may be indicative of ovarian health and oocyte quality. Despite future accurate clinical investigations are absolutely needed, the present analysis may provide a starting point for more accurate oocyte quality estimation and for defining personalised therapies in reproductive medicine.

Genetic characterization of individuals at risk of Alzheimer's disease (AD), i.e. people having amyloid deposits in the brain without symptoms, people suffering from subjective cognitive decline (SCD) or mild cognitive impairment (MCI), has spurred the interests of researchers. However, their pre-dementia genetic profile remains mostly unexplored. In this study, we reviewed the loci related to phenotypes of AD, MCI and SCD from literature and performed the first meta-analyses evaluating the role of apolipoprotein E (APOE) in the risk of conversion from a healthy status to MCI and SCD. For AD dementia risk, an increased number of loci have been identified; to date, 28 genes have been associated with Late Onset AD. In MCI syndrome, APOE is confirmed as a pheno-conversion factor leading from MCI to AD, and clusterin is a promising candidate. Additionally, our meta-analyses revealed APOE as genetic risk factor to convert from a healthy status to MCI [OR = 1.849 (1.587–2.153); P = 2.80  × 10−15] and to a lesser extent from healthy status to SCD [OR = 1.151 (1.015–1.304); P = 0.028]. Thus, we believe that genetic studies in longitudinal SCD and MCI series may provide new therapeutic targets and improve the existing knowledge of AD. This type of studies must be completed on healthy subjects to better understand the natural disease resistance to brain insults and neurodegeneration.

Necrotising enterocolitis (NEC) is an uncommon, but devastating intestinal inflammatory disease that predominantly affects preterm infants. NEC is sometimes dubbed the spectre of neonatal intensive care units, as its onset is insidiously non-specific, and once the disease manifests, the damage inflicted on the baby's intestine is already disastrous. Subsequent sepsis and multi-organ failure entail a mortality of up to 65%. Development of effective treatments for NEC has stagnated, largely because of our lack of understanding of NEC pathogenesis. It is clear, however, that NEC is driven by a profoundly dysregulated immune system. NEC is associated with local increases in pro-inflammatory mediators, e.g. Toll-like receptor (TLR) 4, nuclear factor-κB, tumour necrosis factor, platelet-activating factor (PAF), interleukin (IL)-18, interferon-gamma, IL-6, IL-8 and IL-1β. Deficiencies in counter-regulatory mechanisms, including IL-1 receptor antagonist (IL-1Ra), TLR9, PAF-acetylhydrolase, transforming growth factor beta (TGF-β)1&2, IL-10 and regulatory T cells likely facilitate a pro-inflammatory milieu in the NEC-afflicted intestine. There is insufficient evidence to conclude a predominance of an adaptive Th1-, Th2- or Th17-response in the disease. Our understanding of the accompanying regulation of systemic immunity remains poor; however, IL-1Ra, IL-6, IL-8 and TGF-β1 show promise as biomarkers. Here, we chart the emerging immunological landscape that underpins NEC by reviewing the involvement and potential clinical implications of innate and adaptive immune mediators and their regulation in NEC.

Current therapies to treat Alzheimer's disease (AD) are focused on ameliorating symptoms instead of treating the underlying causes of AD. The accumulation of amyloid β (Aβ) oligomers, whether by an increase in production or by a decrease in clearance, has been described as the seed that initiates the pathological cascade in AD. Developing therapies to target these species is a vital step in improving AD treatment. Aβ-immunotherapy, especially passive immunotherapy, is a promising approach to reduce the Aβ burden. Up to now, several monoclonal antibodies (mAbs) have been tested in clinical trials on humans, but none of them have passed Phase III. In all likelihood, these trials failed mainly because patients with mild-to-moderate AD were recruited, and thus treatment may have been too late to be effective. Therefore, many ongoing clinical trials are being conducted in patients at the prodromal stage. New structures based on antibody fragments have been engineered intending to improve efficacy and safety. This review presents the properties of this variety of developing treatments and provides a perspective on state-of-the-art of passive Aβ-immunotherapy in AD.

Steatosis is an early characteristic in the pathogenesis of fatty liver disease (FLD). Mechanisms of hepatic steatosis are aetiology-dependent. Activation of autophagy in liver ameliorates hepatic steatosis. A modulation of hepatic autophagy affects the degree of hepatocyte steatosis and the progression of FLD as demonstrated by pre-clinical models and clinical trials. This review summarises recent advances on pathophysiological roles of autophagy in hepatic lipid metabolism. A comprehensive regulation of autophagic networks holds promise for the improvement of hepatic steatosis. Autophagic signalling pathway may be a novel therapeutic target against FLD.

Highlights:

• • Hepatic steatosis is a pathological condition wherein vacuoles of triglyceride (TG) fat are overaccumulated in liver because of abnormal metabolism of lipids.

• • Hepatic autophagy regulates lipid metabolism as demonstrated by macrolipophagy in response to starvation and hepatic overabundance of TG in obesity.

• • Autophagic signals are closely associated with apoptotic pathways. There is distinctive relationship between hepatic autophagy and apoptosis, which affects the progression of fatty liver.

• • Regulation of autophagic process can be a novel therapeutic strategy for fatty liver disease.

Eye-derived fluids, including tears, aqueous humour and vitreous humour often contain molecular signatures of ocular disease states. These signatures can be composed of cytokines, chemokines, growth factors, proteases and soluble receptors. However, the small quantities (<10 µl) of these fluids severely limit the detection of these proteins by traditional enzyme-linked immunosorbent assay or Western blot. To maximise the amount of information generated from the analysis of these specimens, many researchers have employed multiplex immunoassay technologies for profiling the expression or modification of multiple proteins from minute sample volumes.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD and causes subsequent pathological changes including cirrhosis and hepatocellular carcinoma. Inflammation is the key pathological change in NASH and involves a series of cytokines and chemokines. The C-X-C motif chemokine 10 (CXCL10), which is known as a pro-inflammation chemokine, was recently proven to play a pivotal role in the pathogenesis of NASH. Hepatic CXCL10 is mainly secreted by hepatocytes and liver sinusoidal endothelium. By binding to its specific receptor CXCR3, CXCL10 recruits activated CXCR3+ T lymphocytes and macrophages to parenchyma and promotes inflammation, apoptosis and fibrosis. The circulating CXCL10 level correlates with the severity of lobular inflammation and is an independent risk factor for NASH patients. Thus, CXCL10 may be both a potential prognostic tool and a therapeutic target for the treatment of patients with NASH. The aim of this review is to highlight the growing advances in basic knowledge and clinical interest of CXCL10 in NASH to propagate new insights into novel pharmacotherapeutic avenues.

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disease caused by hepatic deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme synthesis pathway. The dominant clinical feature is acute neurovisceral attack associated with high production of potentially neurotoxic porphyrin precursors due to increased hepatic heme consumption. Current Standard of Care is based on a down-regulation of hepatic heme synthesis using heme therapy. Recurrent hyper-activation of the hepatic heme synthesis pathway affects about 5% of patients and can be associated with neurological and metabolic manifestations and long-term complications including chronic kidney disease and increased risk of hepatocellular carcinoma. Prophylactic heme infusion is an effective strategy in some of these patients, but it induces tolerance and its frequent application may be associated with thromboembolic disease and hepatic siderosis. Orthotopic liver transplantation is the only curative treatment in patients with recurrent acute attacks. Emerging therapies including replacement enzyme therapy or gene therapies (HMBS-gene transfer and ALAS1-gene expression inhibition) are being developed to improve quality of life, reduce the significant morbidity associated with current therapies and prevent late complications such as hepatocellular cancer or kidney failure in HMBS mutation carriers with long-standing high production of noxious heme precursors. Herein, we provide a critical digest of the recent literature on the topic and a summary of recently developed approaches to AIP treatment and their clinical implications.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterised by lack of expression of oestrogen-, progesterone- and human epidermal growth factor receptors. TNBC, which represents approximately 15% of all mammary tumours, has a poor prognosis because of an aggressive behaviour and the lack of specific treatment. Accordingly, TNBC has become a major focus of research into breast cancer and is now classified into several molecular subtypes, each with a different prognosis. Pathological angiogenesis occurs at a late stage in the proliferation of TNBC and is associated with invasion and metastasis; there is an association with metabolic syndrome. Semaphorins are a versatile family of proteins with multiple roles in angiogenesis, tumour growth and metastasis and may represent a clinically useful focus for therapeutic targeting in this type of breast cancer. Another important field of investigation into the control of pathological angiogenesis is related to the expression of noncoding RNA (ncRNA) – these molecules can be considered as a therapeutic target or as a biomarker. Several molecular agents for intervening in the activity of different signalling pathways are being explored in TNBC, but none has so far proved effective in clinical trials and the disease continues to pose a defining challenge for clinical management as well as innovative cancer research.