scholarly journals Food Supplements to Mitigate Detrimental Effects of Pelvic Radiotherapy

2019 ◽  
Vol 7 (4) ◽  
pp. 97 ◽  
Author(s):  
Charlotte Segers ◽  
Mieke Verslegers ◽  
Sarah Baatout ◽  
Natalie Leys ◽  
Sarah Lebeer ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Cell Types ◽  
Intestinal Wall ◽  
Food Supplements ◽  
Pelvic Radiotherapy ◽  
Pelvic Radiation ◽  
Microbial Dysbiosis ◽  
Radiation Induced

Pelvic radiotherapy has been frequently reported to cause acute and late onset gastrointestinal (GI) toxicities associated with significant morbidity and mortality. Although the underlying mechanisms of pelvic radiation-induced GI toxicity are poorly understood, they are known to involve a complex interplay between all cell types comprising the intestinal wall. Furthermore, increasing evidence states that the human gut microbiome plays a role in the development of radiation-induced health damaging effects. Gut microbial dysbiosis leads to diarrhea and fatigue in half of the patients. As a result, reinforcement of the microbiome has become a hot topic in various medical disciplines. To counteract GI radiotoxicities, apart from traditional pharmacological compounds, adjuvant therapies are being developed including food supplements like vitamins, prebiotics, and probiotics. Despite the easy, cheap, safe, and feasible approach to protect patients against acute radiation-induced toxicity, clinical trials have yielded contradictory results. In this review, a detailed overview is given of the various clinical, intestinal manifestations after pelvic irradiation as well as the role of the gut microbiome herein. Furthermore, whilst discussing possible strategies to prevent these symptoms, food supplements are presented as auspicious, prophylactic, and therapeutic options to mitigate acute pelvic radiation-induced GI injury by exploring their molecular mechanisms of action.

scholarly journals Epigenetic Regulation of the Hippocampus, with Special Reference to Radiation Exposure

2020 ◽  
Vol 21 (24) ◽  
pp. 9514
Author(s):  
Genevieve Saw ◽  
Feng Ru Tang
Keyword(s):  
Epigenetic Regulation ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Epigenetic Changes ◽  
Epigenetic Factors ◽  
Hippocampal Function ◽  
Neuropsychological Disorders ◽  
Radiation Induced ◽  
Non Coding Rnas ◽  
And Function

The hippocampus is crucial in learning, memory and emotion processing, and is involved in the development of different neurological and neuropsychological disorders. Several epigenetic factors, including DNA methylation, histone modifications and non-coding RNAs, have been shown to regulate the development and function of the hippocampus, and the alteration of epigenetic regulation may play important roles in the development of neurocognitive and neurodegenerative diseases. This review summarizes the epigenetic modifications of various cell types and processes within the hippocampus and their resulting effects on cognition, memory and overall hippocampal function. In addition, the effects of exposure to radiation that may induce a myriad of epigenetic changes in the hippocampus are reviewed. By assessing and evaluating the current literature, we hope to prompt a more thorough understanding of the molecular mechanisms that underlie radiation-induced epigenetic changes, an area which can be further explored.

scholarly journals The Role of the Transcription Factor Foxo3 in Hearing Maintenance: Informed Speculation on a New Player in the Cochlea

2016 ◽  
Vol 2016 ◽  
pp. 1-10
Author(s):  
Patricia M. White
Keyword(s):  
Hearing Loss ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Cell Types ◽  
Mouse Genetics ◽  
Molecular Response ◽  
Cellular Processes ◽  
Powerful Approach ◽  
Multiple Cell

Molecular genetics has proven to be a powerful approach for understanding early-onset hearing loss. Recent work in late-onset hearing loss uses mouse genetics to identify molecular mechanisms that promote the maintenance of hearing. One such gene, Foxo3, is ontologically involved in preserving mitochondrial function. Significant evidence exists to support the idea that mitochondrial dysfunction is correlated with and can be causal for hearing loss. Foxo3 is also ontologically implicated in driving the circadian cycle, which has recently been shown to influence the molecular response to noise damage. In this review, the molecular framework connecting these cellular processes is discussed in relation to the cellular pathologies observed in human specimens of late-onset hearing loss. In bringing these observations together, the possibility arises that distinct molecular mechanisms work in multiple cell types to preserve hearing. This diversity offers great opportunities to understand and manipulate genetic processes for therapeutic gain.

scholarly journals Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

2018 ◽  
Vol 132 (5) ◽  
pp. 509-522 ◽  
Author(s):  
Wei Ling Lau ◽  
Javad Savoj ◽  
Michael B. Nakata ◽  
Nosratola D. Vaziri
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Intestinal Wall ◽  
Uremic Toxins ◽  
Blood Levels ◽  
Systemic Effects ◽  
Kidney Fibrosis ◽  
Microbial Dysbiosis

In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

scholarly journals The impact of pelvic radiotherapy on the gut microbiome and its role in radiation-induced diarrhoea: a systematic review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Lina Wang ◽  
Xiaohu Wang ◽  
Guangwen Zhang ◽  
Yan Ma ◽  
Qiuning Zhang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Primary Tumour ◽  
Intestinal Flora ◽  
Radiation Enteritis ◽  
Cochrane Library ◽  
Pelvic Radiotherapy ◽  
Pelvic Malignancies ◽  
Radiation Induced ◽  
The Impact

AbstractPelvic radiotherapy is the key treatment for pelvic malignancies, usually including pelvic primary tumour lesions and lymphatic drainage areas in the pelvic region. Therefore, the intestinal tract in the radiation field is inevitably damaged, a phenomenon clinically referred to as radiation enteritis, and diarrhoea is the most common clinical symptom of radiation enteritis. Therefore, it is necessary to study the mechanism of radiation-induced diarrhoea. It has been found that the gut microbiome plays an important role in the development of diarrhoea in response to pelvic radiotherapy, and the species and distribution of intestinal microbiota are significantly altered in patients after pelvic radiotherapy. In this study, we searched for articles indexed in the Cochrane Library, Web of Science, EMBASE and PubMed databases in English and CNKI, Wanfang data and SINOMED in Chinese from their inception dates through 13 March 2020 to collect studies on the gut microbiome in pelvic radiotherapy patients. Eventually, we included eight studies: one study report on prostatic carcinoma, five studies on gynaecological carcinoma and two papers on pelvic carcinomas. All studies were designed as self-controlled studies, except for one that compared toxicity to nontoxicity. The results from all the studies showed that the diversity of intestinal flora decreased during and after pelvic radiotherapy, and the diversity of intestinal flora decreased significantly in patients with diarrhoea after radiotherapy. Five studies observed that the community composition of the gut microbiota changed at the phylum, order or genus level before, during, and after pelvic radiotherapy at different time points. In addition, the composition of the gut microbiota before radiotherapy was different between patients with postradiotherapy diarrhoea and those without diarrhoea in five studies. However, relevant studies have not reached consistent results regarding the changes in microbiota composition. Changes in the intestinal flora induced by pelvic radiotherapy and their relationship between changes in intestinal flora and the occurrence of radiation-induced diarrhoea (RID) are discussed in this study, providing a theoretical basis for the causes of RID after pelvic radiotherapy.

scholarly journals MO679EFFECTS OF ALANYL-GLUTAMINE SUPPLEMENTED PD FLUID ON THE PLASMA METABOLOME AND GUT MICROBIOME IN EXPERIMENTAL PD*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Jitka Lachova ◽  
Rebecca Herzog ◽  
Florian Wiesenhofer ◽  
Klaus Kratochwill
Keyword(s):  
Gut Microbiome ◽  
Molecular Mechanisms ◽  
Tap Water ◽  
Additional Risk Factor ◽  
Functional Changes ◽  
Microbiome Composition ◽  
Microbial Dysbiosis ◽  
Important Benefit ◽  
Main Driver ◽  
Elevated Creatinine

Abstract Background and Aims Peritoneal dialysis (PD) is associated with morphological and also functional changes to the peritoneum limiting the long-term use. PD and CKD lead to vasculopathy, disrupt the endothelial and peritoneal barrier, but also influence the gut microbiome. Microbial dysbiosis in return is speculated to drive inflammation as an additional risk factor for cardiovascular disease. New PD-fluids that could slow or prevent these processes are needed. Alanyl-glutamine (AlaGln) has immunomodulatory and cytoprotective properties and has been shown to also improve endothelial barrier functions. Our aim is to investigate the effects of AlaGln-supplementation to PD-fluid on the gut microbiome and plasma and effluent metabolome and their interplay. Method Mice (C57/BI6N) underwent a subtotal nephrectomy (5/6 nephrectomy) to induce uraemia. Chronic exposure to PD-fluid was performed for 9 weeks via subcutaneously implanted peritoneal catheters. Mice were exposed daily to 2 ml of commercially available glucose-based PD-fluid (3.86% glucose) without or with the addition of 8 mM AlaGln. Uremic and healthy mice, kept in parallel were used as controls. All mice were fed standard chow and tap water ad libitum. On the last day, blood and an effluent (after a 30 minute dwell) were collected and faecal matter was collected from 3 different sites of the gut (ileum, caecum and colon). The plasma and effluent metabolome were analysed using a targeted approach. 180 metabolites were analysed with a mass spectrometry based kit (Biocrates) in both samples types. Following microbial DNA isolation, the microbiome has been analysed by 16S rRNA sequencing. The experiment was approved by the local animal ethics committee. Results Significantly elevated creatinine values in mice following 5/6 nephrectomy confirmed their uremic status. Significantly different plasma and effluent levels of alanine and glutamine were found in mice exposed to AlaGln supplemented PD-fluid. A correlation analysis of the plasma revealed the uremic status of the mice as main driver of differences whereas the effluent metabolome was mainly changed by PD fluid exposure. Plasma of uremic mice also showed significantly increased levels of a toxic non-proteinogenic amino acid symmetric dimethyl arginine (SDMA) and citrulline. Microbiome analysis yielded over 2800 amplicon sequence variants. Microbiome composition was location specific and influenced by the different treatments. The microbiome data were also correlated with over 130 metabolites in both plasma and PD effluent. Our data showed increased abundance in bacterial family Pseudomonadacea in caecum of uremic mice and positive correlation with the plasma level of trans-tetra-hydroxyproline. Mice exposed to conventional PD fluid had higher abundance of the bacterial class Clostridia in the colon compared to mice with no PD exposition. Conclusion CKD itself and PD-fluid exposure both affect the gut microbiome and the AlaGln-supplementation effects are likely reflected at the level of microbial diversity and functional interaction with metabolites. As next step specific cellular and molecular mechanisms of these effects are analysed. Preservation of mesothelial and also endothelial cellular barrier function could be a clinically important benefit for patients treated with PD, by preventing increased PD-associated pathomechanisms.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Immunomodulatory Effects of Radiotherapy

2020 ◽  
Vol 21 (21) ◽  
pp. 8151
Author(s):  
Sharda Kumari ◽  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Salim Abdisalaam ◽  
Sunil Krishnan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Carbon Particle ◽  
Dna Lesions ◽  
X Rays ◽  
Adaptive Immune ◽  
High Let Radiation ◽  
Different Types ◽  
High Let ◽  
Radiation Induced ◽  
Tumor Death

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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