Molecular Aspects of Medicine最新文献

Glaucoma, the leading cause of irreversible blindness worldwide, is a complex human disease, with both genetic and environmental determinants. The availability of large-scale, population-based cohorts and biobanks, combining genotyping and detailed phenotyping, has greatly accelerated research into the aetiology of glaucoma in recent years. Hypothesis-free genome-wide association studies have furthered our understanding of the complex genetic architecture underpinning the disease, while epidemiological studies have provided advances in the identification and characterisation of environmental risk factors. It is increasingly recognised that the combined effects of genetic and environmental factors may confer a disease risk that reflects a departure from the simple additive effect of the two. These gene-environment interactions have been implicated in a host of complex human diseases, including glaucoma, and have several important diagnostic and therapeutic implications for future clinical practice. Importantly, the ability to modify the risk associated with a particular genetic makeup promises to lead to personalised recommendations for glaucoma prevention, as well as novel treatment approaches in years to come. Here we provide an overview of genetic and environmental risk factors for glaucoma, as well as reviewing the evidence and discussing the implications of gene-environment interactions for the disease.

Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal disease to leverage immune-interception strategies. Therefore, the identification of these neoAgs is an ongoing effort for the development of LS cancer preventive vaccines. In this review, we summarize the computational methods used for in silico neoAg prediction, including their challenges, and the experimental techniques used for in vitro validation of their immunogenicity. In addition, we outline results from past and on-going vaccine clinical trials and highlight avenues for improvement and future directions.

Heart failure is a leading cause of mortality and hospitalization worldwide. Cardiac fibrosis, resulting from the excessive deposition of collagen fibers, is a common feature across the spectrum of conditions converging in heart failure. Eventually, either reparative or reactive in nature, in the long-term cardiac fibrosis contributes to heart failure development and progression and is associated with poor clinical outcomes. Despite this, specific cardiac antifibrotic therapies are lacking, making cardiac fibrosis an urgent unmet medical need. In this context, a better patient phenotyping is needed to characterize the heterogenous features of cardiac fibrosis to advance toward its personalized management. In this review, we will describe the different phenotypes associated with cardiac fibrosis in heart failure and we will focus on the potential usefulness of imaging techniques and circulating biomarkers for the non-invasive characterization and phenotyping of this condition and for tracking its clinical impact. We will also recapitulate the cardiac antifibrotic effects of existing heart failure and non-heart failure drugs and we will discuss potential strategies under preclinical development targeting the activation of cardiac fibroblasts at different levels, as well as targeting additional extracardiac processes.

An increasing number of patients worldwide suffers from chronic kidney disease (CKD). CKD is accompanied by kidney fibrosis, which affects all compartments of the kidney, i.e., the glomeruli, tubulointerstitium, and vasculature. Fibrosis is the best predictor of progression of kidney diseases. Currently, there is no specific anti-fibrotic therapy for kidney patients and invasive renal biopsy remains the only option for specific detection and quantification of kidney fibrosis. Here we review emerging diagnostic approaches and potential therapeutic options for fibrosis. We discuss how translational research could help to establish fibrosis-specific endpoints for clinical trials, leading to improved patient stratification and potentially companion diagnostics, and facilitating and optimizing development of novel anti-fibrotic therapies for kidney patients.

Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action.

The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.

Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with eye drops. A major challenge in the topical treatment of glaucoma patients is the many side effects and the resulting reduced adherence. Side effects may of course be due to the molecular properties of the active pharmaceutical ingredients (APIs). There are currently six different APIs available: prostaglandin analogues, β-adrenergic inhibitors, α-adrenergic agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors and muscarinic 3 agonists. But the additives used in eye drops are also known to cause damage to the ocular surface and to some extent also to the deeper tissues. Said additives are considered inactive molecular components and are added to secure for instance viscosity and pH value, and to prevent contamination. There has been an increasing focus on the harmful effects of preservatives, with the most commonly used preservative benzalkonium chloride (BAK) being particularly controversial. BAK has long been recognized as a toxin that increases the risk of ocular discomfort. This can affect the adherence and ultimately result in lack of disease control. Other issues include the addition of certain buffers, such as phosphates, and varying pH values. This review will address the different molecular components of the IOP-lowering eye drops and what to be aware of when prescribing topical glaucoma treatment.

Pseudoexfoliation is a complex, progressive, and systemic age-related disorder. The early stage of deposition of extracellular fibrillar material on ocular and extraocular tissues is termed as pseudoexfoliation syndrome (PEXS). The severe advanced stage is known as pseudoexfoliation glaucoma (PEXG), which involves increased intraocular pressure and optic nerve damage. Through genome-wide association and candidate gene studies, PEX has been associated with numerous genetic risk variants in various gene loci. However, the genetic basis of the disease fails to explain certain features of PEX pathology, such as the progressive nature of the disease, asymmetric ocular manifestation, age-related onset, and only a subset of PEXS individuals developing PEXG. Increasing evidence shows an interplay of genetic and epigenetic factors in the pathology of complex, multifactorial diseases. In this review, we have discussed the genetic basis of the disease and the emerging contribution of epigenetic regulations in PEX pathogenesis, focusing on DNA methylation and non-coding RNAs. Aberrant methylation patterns, histone modifications, and post-transcriptional regulation by microRNAs lead to aberrant gene expression changes. We have reviewed these aberrant epigenetic changes in PEX pathology and their effect on molecular pathways associated with PEX. We have further discussed some possible genetic/epigenetic-based diagnoses and therapeutics for PEX. Although studies to understand the role of epigenetic regulations in PEX are just emerging, epigenetic modifications contribute significantly to PEX pathogenesis and may pave the way for better and targeted therapeutics.

Most mind boggling diseases are accepted to be impacted by both genetic and environmental elements. As of late, there has been a flood in the improvement of different methodologies, concentrate on plans, and measurable and logical techniques to examine gene-environment cooperations (G × Es) in enormous scope studies including human populaces. The many-sided exchange between genetic elements and environmental openings has long charmed the consideration of clinicians and researchers looking to grasp the complicated starting points of diseases. While single variables can add to disease, the blend of genetic variations and environmental openings frequently decides disease risk. The fundamental point of this paper is to talk about the Gene-Environment Associations That Impact CVD, Lipid Characteristics, Obesity, Diabetes, and Hypertension Have all the earmarks of being Ready to Impact Gene Therapy. This survey paper investigates the meaning of gene-environment collaborations (G × E) in disease advancement. The intricacy of genetic and environmental communications in disease causation is explained, underlining the multifactorial idea of many circumstances. The job of gene-environment cooperations in cardiovascular disease, lipid digestion, diabetes, obesity, and hypertension is investigated. This audit fixates on Gene by Environment (G × E) collaborations, investigating their importance in disease etiology.

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons of the retina. Glaucoma is the most common cause of irreversible blindness and affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, and elevated intraocular pressure. Current strategies only target intraocular pressure management and do not directly target the neurodegenerative processes occurring at the level of the retinal ganglion cell. Despite strategies to manage intraocular pressure, as many as 40% of glaucoma patients progress to blindness in at least one eye during their lifetime. As such, neuroprotective strategies that target the retinal ganglion cell and these neurodegenerative processes directly are of great therapeutic need. This review will cover the recent advances from basic biology to on-going clinical trials for neuroprotection in glaucoma covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, and neuroinflammation. With an increased understanding of both the basic and clinical mechanisms of the disease, we are closer than ever to a neuroprotective strategy for glaucoma.

Fibrosis, or tissue scarring, develops as a pathological deviation from the physiological wound healing response and can occur in various organs such as the heart, lung, liver, kidney, skin, and bone marrow. Organ fibrosis significantly contributes to global morbidity and mortality. A broad spectrum of etiologies can cause fibrosis, including acute and chronic ischemia, hypertension, chronic viral infection (e.g., viral hepatitis), environmental exposure (e.g., pneumoconiosis, alcohol, nutrition, smoking) and genetic diseases (e.g., cystic fibrosis, alpha-1-antitrypsin deficiency). Common mechanisms across organs and disease etiologies involve a sustained injury to parenchymal cells that triggers a wound healing response, which becomes deregulated in the disease process. A transformation of resting fibroblasts into myofibroblasts with excessive extracellular matrix production constitutes the hallmark of disease, however, multiple other cell types such as immune cells, predominantly monocytes/macrophages, endothelial cells, and parenchymal cells form a complex network of profibrotic cellular crosstalk. Across organs, leading mediators include growth factors like transforming growth factor-β and platelet-derived growth factor, cytokines like interleukin-10, interleukin-13, interleukin-17, and danger-associated molecular patterns. More recently, insights into fibrosis regression and resolution of chronic conditions have deepened our understanding of beneficial, protective effects of immune cells, soluble mediators and intracellular signaling. Further in-depth insights into the mechanisms of fibrogenesis can provide the rationale for therapeutic interventions and the development of targeted antifibrotic agents. This review gives insight into shared responses and cellular mechanisms across organs and etiologies, aiming to paint a comprehensive picture of fibrotic diseases in both experimental settings and in human pathology.