Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

The molecular processes that predispose the development of Barrett’s esophagus (BE) towards esophageal adenocarcinoma (EAC) induced by gastrointestinal reflux disease (GERD) are still under investigation. In this study, based on a scientific literature screening and an analysis of clinical datasets, we selected a panel of 20 genes covering BE- and EAC-specific molecular markers (FZD5, IFNGR1, IL1A, IL1B, IL1R1, IL1RN, KRT4, KRT8, KRT15, KRT18, NFKBIL1, PTGS1, PTGS2, SOCS3, SOX4, SOX9, SOX15, TIMP1, TMEM2, TNFRSF10B). Furthermore, we aimed to reflect these alterations within an experimental and translational in vitro model of BE to EAC progression. We performed a comparison between expression profiles in GSE clinical databases with an in vitro model of GERD involving a BE cell line (BAR-T) and EAC cell lines (OE33 and OE19). Molecular responses of cells treated with acidified bile mixture (BM) at concentration of 100 and 250 μM for 30 min per day were evaluated. We also determined a basal mRNA expression within untreated, wild type cell lines on subsequent stages of BE and EAC development. We observed that an appropriately optimized in vitro model based on the combination of BAR-T, OE33 and OE19 cell lines reflects in 65% and more the clinical molecular alterations observed during BE and EAC development. We also confirmed previous observations that exposure to BM (GERD in vitro) activated carcinogenesis in non-dysplastic cells, inducing molecular alternations in the advanced stages of BE. We conclude that it is possible to induce, to a high extent, the molecular profile observed clinically within appropriately and carefully optimized experimental models, triggering EAC development. This experimental scheme and molecular marker panel might be implemented in further research, e.g., aiming to develop and evaluate novel compounds and prodrugs targeting GERD as well as BE and EAC prevention and treatment.     

Obesity as a Risk Factor for Dementia and Alzheimer’s Disease: The Role of Leptin

Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.     

Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways of the Disease

Alzheimer’s disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.     

Physical Exercise,a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients

This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer’s disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual’s mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.     

The Potential Role of miRNA-Regulated Autophagy in Alzheimer’s Disease

As a neurodegenerative disease, Alzheimer’s disease (AD) shows a higher incidence during the aging process, mainly revealing the characteristics of a significant decrease in cognition, uncontrolled emotion, and reduced learning and memory capacity, even leading to death. In the prevention and treatment of AD, some pharmacological therapy has been applied in clinical practice. Unfortunately, there are still limited effective treatments for AD due to the absence of clear and defined targets. Currently, it is recognized that the leading causes of AD include amyloid-β peptide (Aβ) deposition, hyperphosphorylation of tau protein, neurofibrillary tangles, mitochondrial dysfunction, and inflammation. With in-depth mechanistic exploration, it has been found that these causes are highly correlated with the dysfunctional status of autophagy. Numerous experimental results have also confirmed that the development and progression of AD is accompanied by an abnormal functional status of autophagy; therefore, regulating the functional status of autophagy has become one of the important strategies for alleviating or arresting the progression of AD. With the increasing attention given to microRNAs (miRNAs), more and more studies have found that a series of miRNAs are involved in the development and progression of AD through the indirect regulation of autophagy. Therefore, regulating autophagy through targeting these miRNAs may be an essential breakthrough for the prevention and treatment of AD. This article summarizes the regulation of miRNAs in autophagy, with the aim of providing a new theoretical reference point for the prevention and treatment of AD through the indirect regulation of miRNA-mediated autophagy.     

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.     

Long Non-Coding RNAs,Extracellular Vesicles and Inflammation in Alzheimer’s Disease

Alzheimer’s Disease (AD) has currently no effective treatment; however, preventive measures have the potential to reduce AD risk. Thus, accurate and early prediction of risk is an important strategy to alleviate the AD burden. Neuroinflammation is a major factor prompting the onset of the disease. Inflammation exerts its toxic effect via multiple mechanisms. Amongst others, it is affecting gene expression via modulation of non-coding RNAs (ncRNAs), such as miRNAs. Recent evidence supports that inflammation can also affect long non-coding RNA (lncRNA) expression. While the association between miRNAs and inflammation in AD has been studied, the role of lncRNAs in neurodegenerative diseases has been less explored. In this review, we focus on lncRNAs and inflammation in the context of AD. Furthermore, since plasma-isolated extracellular vesicles (EVs) are increasingly recognized as an effective monitoring strategy for brain pathologies, we have focused on the studies reporting dysregulated lncRNAs in EVs isolated from AD patients and controls. The revised literature shows a positive association between pro-inflammatory lncRNAs and AD. However, the reports evaluating lncRNA alterations in EVs isolated from the plasma of patients and controls, although still limited, confirm the value of specific lncRNAs associated with AD as reliable biomarkers. This is an emerging field that will open new avenues to improve risk prediction and patient stratification, and may lead to the discovery of potential novel therapeutic targets for AD.     

Tear Biomarkers in Alzheimer’s and Parkinson’s Diseases,and Multiple Sclerosis: Implications for Diagnosis (Systematic Review)

Biological material is one of the most important aspects that allow for the correct diagnosis of the disease, and tears are an interesting subject of research because of the simplicity of collection, as the well as the relation to the components similar to other body fluids. In this review, biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) in tears are investigated and analyzed. Records were obtained from the PubMed and Google Scholar databases in a timeline of 2015–2022. The keywords were: tear film/tear biochemistry/tear biomarkers + diseases (AD, PD, or MS). The recent original studies were analyzed, discussed, and biomarkers present in tears that can be used for the diagnosis and management of AD, PD, and MS diseases were shown. α-synTotal and α-synOligo, lactoferrin, norepinephrine, adrenaline, epinephrine, dopamine, α-2-macroglobulin, proteins involved in immune response, lipid metabolism and oxidative stress, apolipoprotein superfamily, and others were shown to be biomarkers in PD. For AD as potential biomarkers, there are: lipocalin-1, lysozyme-C, and lacritin, amyloid proteins, t-Tau, p-Tau; for MS there are: oligoclonal bands, lipids containing choline, free carnitine, acylcarnitines, and some amino acids. Information systematized in this review provides interesting data and new insight to help improve clinical outcomes for patients with neurodegenerative disorders.     

Highlighting Immune System and Stress in Major Depressive Disorder,Parkinson’s,and Alzheimer’s Diseases,with a Connection with Serotonin

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer’s, and Parkinson’s to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions.     

Activation of Endogenous Retrovirus,Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer’s Disease

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.     

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer’s Disease,Parkinson’s Disease and Multiple Sclerosis

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.     

Novel Models of Crohn’s Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells

Crohn’s disease remains one of the challenging problems of modern medicine, and the development of new and effective and safer treatments against it is a dynamic field of research. To make such developments possible, it is important to understand the pathologic processes underlying the onset and progression of Crohn’s disease at the molecular and cellular levels. During the recent years, the involvement of mitochondrial dysfunction and associated chronic inflammation in these processes became evident. In this review, we discuss the published works on pathogenetic models of Crohn’s disease. These models make studying the role of mitochondrial dysfunction in the disease pathogenesis possible and advances the development of novel therapies.     

Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer’s Disease

The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.     

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass.     

Effect of Obesity and High-Density Lipoprotein Concentration on the Pathological Characteristics of Alzheimer’s Disease in High-Fat Diet-Fed Mice

The typical pathological features of Alzheimer’s disease (AD) are the accumulation of amyloid plaques in the brain and reactivity of glial cells such as astrocytes and microglia. Clinically, the development of AD and obesity are known to be correlated. In this study, we analyzed the changes in AD pathological characteristics in 5XFAD mice after obesity induction through a high-fat diet (HFD). Surprisingly, high-density lipoprotein and apolipoprotein AI (APOA-I) serum levels were increased without low-density lipoprotein alteration in both HFD groups. The reactivity of astrocytes and microglia in the dentate gyrus of the hippocampus and fornix of the hypothalamus in 5XFAD mice was decreased in the transgenic (TG)-HFD high group. Finally, the accumulation of amyloid plaques in the dentate gyrus region of the hippocampus was also significantly decreased in the TG-HFD high group. These results suggest that increased high-density lipoprotein level, especially with increased APOA-I serum level, alleviates the pathological features of AD and could be a new potential therapeutic strategy for AD treatment.     

Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington’s Disease

Accumulation of misfolded proteins is a common phenomenon of several neurodegenerative diseases. The misfolding of proteins due to abnormal polyglutamine (PolyQ) expansions are linked to the development of PolyQ diseases including Huntington’s disease (HD). Though the genetic basis of PolyQ repeats in HD remains prominent, the primary molecular basis mediated by PolyQ toxicity remains elusive. Accumulation of misfolded proteins in the ER or disruption of ER homeostasis causes ER stress and activates an evolutionarily conserved pathway called Unfolded protein response (UPR). Protein homeostasis disruption at organelle level involving UPR or ER stress response pathways are found to be linked to HD. Due to dynamic intricate connections between ER and mitochondria, proteins at ER-mitochondria contact sites (mitochondria associated ER membranes or MAMs) play a significant role in HD development. The current review aims at highlighting the most updated information about different UPR pathways and their involvement in HD disease progression. Moreover, the role of MAMs in HD progression has also been discussed. In the end, the review has focused on the therapeutic interventions responsible for ameliorating diseased states via modulating either ER stress response proteins or modulating the expression of ER-mitochondrial contact proteins.     

Role of Impaired Mitochondrial Dynamics Processes in the Pathogenesis of Alzheimer’s Disease

Mitochondrial dysfunction is now recognized as a contributing factor to neurodegenerative diseases, including Alzheimer’s disease (AD). Mitochondria are signaling organelles with a variety of functions ranging from energy production to the regulation of cellular metabolism, energy homeostasis, and response to stress. The successful functioning of these complex processes is critically dependent on the accuracy of mitochondrial dynamics, which includes the ability of mitochondria to change shape and position in the cell, which is necessary to maintain proper function and quality control, especially in polarized cells such as neurons. There has been much evidence to suggest that the disruption of mitochondrial dynamics may play a critical role in the pathogenesis of AD. This review highlights aspects of altered mitochondrial dynamics in AD that may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative treatment approach.     

Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose,Bone Marrow,Placenta and Wharton’s Jelly

Mesenchymal stem cells (MSCs) have the potential to be a viable therapy against various diseases due to their paracrine effects, such as secretion of immunomodulatory, trophic and protective factors. These cells are known to be distributed within various organs and tissues. Although they possess the same characteristics, MSCs from different sources are believed to have different secretion potentials and patterns, which may influence their therapeutic effects in disease environments. We characterized the protein secretome of adipose (AD), bone marrow (BM), placenta (PL), and Wharton’s jelly (WJ)-derived human MSCs by using conditioned media and analyzing the secretome by mass spectrometry and follow-up bioinformatics. Each MSC secretome profile had distinct characteristics depending on the source. However, the functional analyses of the secretome from different sources showed that they share similar characteristics, such as cell migration and negative regulation of programmed cell death, even though differences in the composition of the secretome exist. This study shows that the secretome of fetal-derived MSCs, such as PL and WJ, had a more diverse composition than that of AD and BM-derived MSCs, and it was assumed that their therapeutic potential was greater because of these properties.