100,340 research outputs found
The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways
No full textWe focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130- and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology
Micro-RNAs: Crossroads between the exposure to environmental particulate pollution and the obstructive pulmonary disease
No full textEnvironmental pollution has reached a global echo and represents a serious problem for human health. Air pollution encompasses a set of hazardous substances, such as particulate matter and heavy metals (e.g., cadmium, lead, and arsenic), and has a strong impact on the environment by affecting groundwater, soil, and air. An adaptive response to environmental cues is essential for human survival, which is associated with the induction of adaptive phenotypes. The epigenetic mechanisms regulating the expression patterns of several genes are promising candidates to provide mechanistic and prognostic insights into this. Micro-RNAs (miRNAs) fulfil these features given their ability to respond to environmental factors and their critical role in determining phenotypes. These molecules are present in extracellular fluids, and their expression patterns are organ-, tissue-, or cell-specific. Moreover, the experimental settings for their quantitative and qualitative analysis are robust, standardized, and inexpensive. In this review, we provide an update on the role of miRNAs as suitable tools for understanding the mechanisms behind the physiopathological response to toxicants and the prognostic value of their expression pattern associable with specific exposures. We look at the mechanistic evidence associable to the role of miRNAs in the processes leading to environmental-induced pulmonary disease (i.e., chronic obstructive pulmonary disease)
Long non-coding RNAs in regulation of adipogenesis and adipose tissue function
No full textComplex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead to several metabolic diseases including obesity or type 2 diabetes. Here, adipogenesis appears to be a process characterized by an intricate network that involves many transcription factors and long noncoding RNAs (lncRNAs) that regulate gene expression. LncRNAs are being investigated to determine their contribution to adipose tissue development and function. LncRNAs possess multiple cellular functions, and they regulate chromatin remodeling, along with transcriptional and post-transcriptional events; in this way, they affect gene expression. New investigations have demonstrated the pivotal role of these molecules in modulating white and brown/beige adipogenic tissue development and activity. This review aims to provide an update on the role of lncRNAs in adipogenesis and adipose tissue function to promote identification of new drug targets for treating obesity and related metabolic diseases
Nanotechnology-Based Polyphenol Delivery: A Novel Therapeutic Strategy for the Treatment of Age-Related Neurodegenerative Disorder
No full textAge is the major risk factor for the development and progression of Neurodegenerative Diseases (ND). The extension of lifespan is considered a leading cause of the increase in ND prevalence, especially in developing countries. Currently, there is no cure for any of them; thus, the challenge for physicians and researchers is to discover therapeutic strategies able to slow down neurodegeneration and/or improve the patient’s quality of life. In addition to genetics and environmental stressors, the increase in cellular oxidative stress as one of the potential risk factors in ND has been demonstrated. Over the past years the scientific community has focused on the antioxidant properties of a heterogeneous class of natural compounds, known as nutraceuticals, such as vitamins, carotenoids and polyphenols. Among polyphenols, curcumin, resveratrol and tea polyphenols are the most extensively investigated given their therapeutic potential for ND treatment. Despite the strong antioxidant activity of polyphenols, their low bioavailability and rapid metabolism are the major issues that affect their neuroprotective potentiality. A promising solution lies in polymeric nanoparticle-based polyphenol delivery systems that prevent the degradation of bioactive compounds and enhance their absorption and bioavailability. Currently, food-grade lipid-based nanoparticles, polysaccharide nanoparticles, nanoemulsions, biopolymeric nanoparticles, nanocomplexes (proteins, carbohydrates) and copolymers (protein-carbohydrate conjugates) are highly investigated nanoparticle systems to enhance the bioavailability of polyphenols. The high potential of nanoparticle-basedsystems in nutraceutical delivery might make them a good therapeutic strategy for the treatment of ND
Polyphenols, the healthy brand of olive oil: Insights and perspectives
No full textGiven their beneficial potential on human health, plant food bioactive molecules are important components influencing nutrition. Polyphenols have been widely acknowledged for their potentially protective role against several complex diseases. In particular, the polyphenols of olive oil (OOPs) emerge as the key components of many healthy diets and have been widely studied for their beneficial properties. The qualitative and quantitative profile defining the composition of olive oil phenolic molecules as well as their absorbance and metabolism once ingested are key aspects that need to be considered to fully understand the health potential of these molecules. In this review, we provide an overview of the key aspects influencing these variations by focusing on the factors influencing the biosynthesis of OOPs and the findings about their absorption and metabolism. Despite the encouraging evidence, the health potential of OOPs is still debated due to limitations in current studies. Clinical trials are necessary to fully understand and validate the beneficial effects of olive oil and OOPs on human health. We provide an update of the clinical trials based on olive oil and/or OOPs that aim to understand their beneficial effects. Tailored studies are needed to standardize the polyphenolic distribution and understand the variables associated with phenol-enriched OO. An in-depth knowledge of the steps that occur following polyphenol ingestion may reveal useful insights to be used in clinical settings for the prevention and treatment of many diseases
Partial silencing of methyl cytosine protein binding 2 (MECP2) in mesenchymal stem cells induces senescence with an increase in damaged DNA
No full textDNA methylation is an epigenetic modification that occurs almost exclusively on CpG dinucleotides. MECP2 is a member of a family of proteins that preferentially bind to methylated CpGs. We analyzed the contribution of MECP2 to the physiology of mesenchymal stem cells (MSCs). Partial silencing of MECP2 in human MSCs induced a significant reduction of S-phase cells, along with an increase in G(1) cells. These changes were accompanied by a reduction of apoptosis, the triggering of senescence, a decrease in telomerase activity, and the down-regulation of genes involved in maintaining stem cell properties. Senescence appeared to rely on impairment of DNA damage repair and seemed to occur through RB- and P53-related pathways. The effects of MECP2 silencing could be related to the modification of the DNA methylation status. Our results indicate that the silencing of MECP2 induces an increase in methylated cytosines in the genome. Nevertheless, MECP2 partial silencing did not change the methylation of promoters, whose expression is affected by MECP2 down-regulation
Nano-delivery systems for encapsulation of dietary polyphenols: an experimental approach for neurodegenerative diseases and brain tumors
No full textNeurodegenerative diseases (NDs) and brain tumors are severe, disabling, and incurable disorders that represent a critical problem regarding human suffering and the economic burden on the healthcare system. Because of the lack of effective therapies to treat NDs and brain tumors, the challenge for physicians is to discover new drugs to improve their patients’ quality of life. In addition to risk factors such as genetics and environmental influences, increased cellular oxidative stress has been reported as one of the potential common etiologies in both disorders.
Given their antioxidant and anti-inflammatory potential, dietary polyphenols are considered to be one of the most bioactive natural agents in chronic disease prevention and treatment. Despite the protective activity of polyphenols, their inefficient delivery systems and poor bioavailability strongly limit their use in medicine and functional food. A potential solution lies in polymeric nanoparticle-based polyphenol delivery systems that are able to enhance their absorption across the gastrointestinal tract, improve their bioavailability, and transport them to target organs.
In the present manuscript, we provide an overview of the primary polyphenols used for ND and brain tumor prevention and treatment by focusing on recent findings, the principal factors limiting their application in clinical practice, and a promising delivery strategy to improve their bioavailability
A case report: bone marrow mesenchymal stem cells from a Rett syndrome patient are prone to senescence and show a lower degree of apoptosis
No full textRett syndrome (RTT) is one of the most common genetic diseases responsible for a progressive disabling neurodevelopmental disorder. Mutations in the MeCP2 gene were identified in the great majority of RTT patients. MeCP2 protein binds to methylated DNA and produces changes in chromatin structure. This is a key event in regulation of gene expression. It has been suggested that MeCP2 might be important for neuronal development. Moreover, the frequent occurrence of osteoporosis and scoliosis in RTT patients suggests impaired bone formation and/or remodeling. Mesenchymal stem cells (MSCs) can differentiate as mesodermal cells such as bone, cartilage cells, and adipocytes. MSCs have been shown to possess great somatic plasticity; in fact, they can differentiate as neurons and astrocytes. We studied RTT patients' MSCs because they are progenitors of osteocytes, and it has been suggested that RTT patients' osteogenesis could be impaired. Moreover, MSCs might represent a useful model for the study of neurogenesis. MSCs from RTT patient showed precocious signs of senescence in a comparison with the MSCs of healthy-patient control groups. This was in agreement with the reduced gene-expression in the control of stem cell self-renewal and upregulation of lineage specific genes, such as those involved in osteogenesis and neural development. Control groups enabled us to observe a lower degree of apoptosis in RTT patient cells. This means that aberrant stem/progenitor cells, instead of being eliminated, can survive and become senescent. Our research provides a new insight into RTT syndrome. Senescence phenomena could be involved in triggering RTT syndrome-associated diseases
In vitro studies suggest reduced expression of methyl cytosine protein binding 2 (MECP2) affects cell commitment and maintenance in neurons by triggering senescence, new perspective for Rett syndrome
No full textIntroduction: Methyl cytosine protein binding 2 (MECP2) binds preferentially to methylated CpGs and regulates gene expression by causing changes in chromatin struc- ture. The mechanism by which impaired MECP2 activity can induce pathological abnormalities in the nervous system of patients with Rett syndrome (RTT) remains unknown. Studies in different animal models have produced conflicting results. In a mouse model of RTT syndrome, the results indicate that MECP2 is involved in the maturation and maintenance of neurons, whereas in Xenopus embryos, MECP2 muta- tions seem to affect neural cell fate decisions. Material and methods: To gain further insight into the role of MECP2 in human neurogenesis, we compared the neural differentiation process in mesenchymal stem cells (MSCs) obtained from a RTT patient and from healthy donors. We further analyzed neural differentiation in a human neuroblastoma cell line carry- ing a partially silenced MECP2 gene. Results: Senescence and reduced ex- pression of neural markers were ob- served in proliferating and differen- tiating MSCs from the RTT patient, which suggests that impaired activity of MECP2 protein may impair neural differentiation, as observed in RTT patients. Next, we used an inducible expression system to silence MECP2 in neuroblastoma cells before and af- ter the induction of neural differenti- ation via retinoic acid treatment. This approach was used to test whether MECP2 inactivation affected the cell fate of neural progenitors and/or neuronal differentiation and mainte- nance. Conclusion: Overall, our data suggest that neural cell fate and neuronal maintenance may be perturbed by senescence triggered by impaired MECP2 activity either before or after neural differentiation
The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases
No full textAutophagy is the major intracellular machinery for degrading proteins, lipids, polysaccharides, and organelles. This cellular process is essential for the maintenance of the correct cellular balance in both physiological and stress conditions. Because of its role in maintaining cellular homeostasis, dysregulation of autophagy leads to various disease manifestations, such as inflammation, metabolic alterations, aging, and neurodegeneration. A common feature of many neurologic and neuromuscular diseases is the alteration of the autophagy-lysosomal pathways. For this reason, autophagy is considered a target for the prevention and/or cure of these diseases. Dietary intake of polyphenols has been demonstrated to prevent/ameliorate several of these diseases. Thus, natural products that can modulate the autophagy machinery are considered a promising therapeutic strategy. In particular, curcumin, a phenolic compound widely used as a dietary supplement, exerts an important effect in modulating autophagy. Herein, we report on the current knowledge concerning the role of curcumin in modulating the autophagy machinery in various neurological and neuromuscular diseases as well as its role in restoring the autophagy molecular mechanism in several cell types that have different effects on the progression of neurological and neuromuscular disorders
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