Alzheimer's disease (AD) is a devastating disorder that strikes 1 in 10 Americans over the age of 65, and almost half of all Americans over 85years old. The odds of an individual developing AD double ...every five years after the age of 65. While it has become increasingly common to meet heart attack or cancer survivors, there are no AD survivors. There is mounting evidence that dietary polyphenols, including resveratrol, may beneficially influence AD. Based on this consideration, several studies reported in the last few years were designed to validate sensitive and reliable translational tools to mechanistically characterize brain bioavailable polyphenols as disease-modifying agents to help prevent the onset of AD dementia and other neurodegenerative disorders. Several research groups worldwide with expertise in AD, plant biology, nutritional sciences, and botanical sciences have reported very high quality studies that ultimately provided the necessary information showing that polyphenols and their metabolites, which come from several dietary sources, including grapes, cocoa etc., are capable of preventing AD. The ultimate goal of these studies was to provide novel strategies to prevent the disease even before the onset of clinical symptoms. The studies discussed in this review article provide support that the information gathered in the last few years of research will have a major impact on AD prevention by providing vital knowledge on the protective roles of polyphenols, including resveratrol. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.
•Polyphenols and their metabolites are capable of preventing Alzheimer's disease.•The direct molecular targets of resveratrol, in vitro and in vivo, are unknown.•Certain polyphenolic preparations interfere with aggregation of β-amyloid peptides.
Dietary fibers are metabolized by gastrointestinal (GI) bacteria into short-chain fatty acids (SCFAs). We investigated the potential role of these SCFAs in β-amyloid (Aβ) mediated pathological ...processes that play key roles in Alzheimer's disease (AD) pathogenesis.
Multiple complementary assays were used to investigate individual SCFAs for their dose-responsive effects in interfering with the assembly of Aβß1-40 and Aβ1-42 peptides into soluble neurotoxic Aβ aggregates.
We found that several select SCFAs are capable of potently inhibiting Aβ aggregations, in vitro.
Our studies support the hypothesis that intestinal microbiota may help protect against AD, in part, by supporting the generation of select SCFAs, which interfere with the formation of toxic soluble Aβ aggregates.
A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to ...understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.
Major depressive disorder is associated with abnormalities in the brain and the immune system. Chronic stress in animals showed that epigenetic and inflammatory mechanisms play important roles in ...mediating resilience and susceptibility to depression. Here, through a high-throughput screening, we identify two phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc) that are effective in promoting resilience against stress by modulating brain synaptic plasticity and peripheral inflammation. DHCA/Mal-gluc also significantly reduces depression-like phenotypes in a mouse model of increased systemic inflammation induced by transplantation of hematopoietic progenitor cells from stress-susceptible mice. DHCA reduces pro-inflammatory interleukin 6 (IL-6) generations by inhibiting DNA methylation at the CpG-rich IL-6 sequences introns 1 and 3, while Mal-gluc modulates synaptic plasticity by increasing histone acetylation of the regulatory sequences of the Rac1 gene. Peripheral inflammation and synaptic maladaptation are in line with newly hypothesized clinical intervention targets for depression that are not addressed by currently available antidepressants.
Dietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend upon the bioavailability of ...their phenolic metabolites derivatives, which are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. This study examined the role of the gut microbiota in the ability of BDPP to prevent memory impairment in response to SD. C57BL6/J mice, treated with antibiotics mix (ABX) or BDPP or both, were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. We report that the beneficial effect of BDPP on memory in SD is attenuated by ABX-induced dysbiosis. We identified specific communities of fecal microbiota that are associated with the bioavailability of BDPP-derived phenolic acids, which in turn, are associated with memory promotion. These results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols' cognitive resilience property. Our findings provide a preclinical model with which to test the causal association of gut microbiota-polyphenols, with the ultimate goal of potential developing dietary polyphenols for the prevention/treatment of cognitive impairment.
Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. Extensive clinical and genomic studies have revealed biomarkers, ...risk factors, pathways, and targets of AD in the past decade. However, the exact molecular basis of AD development and progression remains elusive. The emerging single-cell sequencing technology can potentially provide cell-level insights into the disease. Here we systematically review the state-of-the-art bioinformatics approaches to analyze single-cell sequencing data and their applications to AD in 14 major directions, including 1) quality control and normalization, 2) dimension reduction and feature extraction, 3) cell clustering analysis, 4) cell type inference and annotation, 5) differential expression, 6) trajectory inference, 7) copy number variation analysis, 8) integration of single-cell multi-omics, 9) epigenomic analysis, 10) gene network inference, 11) prioritization of cell subpopulations, 12) integrative analysis of human and mouse sc-RNA-seq data, 13) spatial transcriptomics, and 14) comparison of single cell AD mouse model studies and single cell human AD studies. We also address challenges in using human postmortem and mouse tissues and outline future developments in single cell sequencing data analysis. Importantly, we have implemented our recommended workflow for each major analytic direction and applied them to a large single nucleus RNA-sequencing (snRNA-seq) dataset in AD. Key analytic results are reported while the scripts and the data are shared with the research community through GitHub. In summary, this comprehensive review provides insights into various approaches to analyze single cell sequencing data and offers specific guidelines for study design and a variety of analytic directions. The review and the accompanied software tools will serve as a valuable resource for studying cellular and molecular mechanisms of AD, other diseases, or biological systems at the single cell level.
Objective
To review the urodynamic outcomes, renal function and metabolic complications after augmentation cystoplasty with at least 10 years of follow‐up.
Methods
Augmentation cystoplasty performed ...in two tertiary referral centers from 1995 to 2004 were reviewed. Ten years or more postoperative course was studied by review of the clinical notes, urodynamic reports and laboratory results.
Results
A total of 40 patients were included in this study. The mean age at surgery was 43 years, and 47.5% of patients were female. Median follow up was 13 years. Bladder capacity significantly increased from 283 ± 151 to 492 ± 123 mL (P < 0.01), with a percentage change of +130%. The compliance of the bladder was increased by 87%, and detrusor overactivity decreased by 54.2%. There were no significant changes in preoperative and postoperative estimated glomerular filtration rate (68.3 mL/min vs 76.6 mL/min, P = 0.798). Three patients (7.5%) had more than one episode of symptomatic urinary tract infection per year.
Conclusion
The present study confirms the effectiveness of augmentation cystoplasty in increasing bladder capacity, improving bladder compliance and reducing detrusor overactivity. The preservation of renal function and low metabolic complication rate provide solid evidence for carrying out this time‐honored procedure in patients with neurogenic or non‐neurogenic bladder dysfunction.
Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is ...limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain‐targeted polyphenols for potential beneficial AD disease‐modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle‐control treatment, one of the brain‐targeted polyphenol metabolites, quercetin‐3‐O‐glucuronide, significantly reduced the generation of β‐amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain‐targeted metabolite, malvidin‐3‐O‐glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo‐induced cross‐linking of unmodified proteins (PICUP) technique, we found that quercetin‐3‐O‐glucuronide is also capable of interfering with the initial protein‐protein interaction of Aβ1–40 and Aβ1–42 that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin‐3‐O‐glucuronide treatment, compared to vehicle‐control treatment, significantly improved AD‐type deficits in hippocampal formation basal synaptic transmission and long‐term potentiation, possibly through mechanisms involving the activation of the c‐Jun N‐terminal kinases and the mitogen‐activated protein kinase signaling pathways. Brain‐targeted quercetin‐3‐O‐glucuronide may simultaneously modulate multiple independent AD disease‐modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.—Ho, L., Ferruzzi, M. G., Janle, E. M., Wang, J., Gong, B., Chen, T.‐Y., Lobo, J., Cooper, B., Wu, Q. L., Talcott, S. T., Percival, S. S., Simon, J. E., Pasinetti, G. M. Identification of brain‐targeted bioactive dietary quercetin‐3‐O‐glucuronide as a novel intervention for Alzheimer's disease. FASEB J. 27, 769–781 (2013). www.fasebj.org
Objective
To formulate consensus statements to facilitate physician management strategies for patients with clinically localized prostate cancer (PCa) in Hong Kong by jointly convening a panel of 12 ...experts from the two local professional organizations representing PCa specialists, who had previously established consensus statements on the management of metastatic PCa for the locality.
Methods
Through a series of meetings, the panellists discussed their clinical experience and the published evidence regarding various areas of the management of localized PCa, then drafted consensus statements. At the final meeting, each drafted statement was voted on by every panellist based on its practicability of recommendation in the locality.
Results
A total of 76 consensus statements were ultimately accepted and established by panel voting.
Conclusion
Derived from the recent evidence and major overseas guidelines, along with local clinical experience and practicability, the consensus statements were aimed to serve as a practical reference for physicians in Hong Kong for the management of localized PCa.
Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson's disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The ...spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show
ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.
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