Molecular Aspects of Medicine最新文献

Microglia are resident myeloid cells in the central nervous system (CNS) with a unique developmental origin, playing essential roles in developing and maintaining the CNS environment. Recent studies have revealed the involvement of microglia in neurodegenerative diseases, such as Alzheimer's disease, through the modulation of neuroinflammation. Several members of the Siglec family of sialic acid recognition proteins are expressed on microglia. Since the discovery of the genetic association between a polymorphism in the CD33 gene and late-onset Alzheimer's disease, significant efforts have been made to elucidate the molecular mechanism underlying the association between the polymorphism and Alzheimer's disease. Furthermore, recent studies have revealed additional potential associations between Siglecs and Alzheimer's disease, implying that the reduced signal from inhibitory Siglec may have an overall protective effect in lowering the disease risk. Evidences suggesting the involvement of Siglecs in other neurodegenerative diseases are also emerging. These findings could help us predict the roles of Siglecs in other neurodegenerative diseases. However, little is known about the functionally relevant Siglec ligands in the brain, which represents a new frontier. Understanding how microglial Siglecs and their ligands in CNS contribute to the regulation of CNS homeostasis and pathogenesis of neurodegenerative diseases may provide us with a new avenue for disease prevention and intervention.

Sialic-acid-binding immunoglobulin-like lectins are cell surface immune receptors known as Siglecs that play a paramount role as modulators of immunity. In recent years, research has underscored how the underlaying biology of this family of receptors influences the outcome of viral infections. While Siglecs are needed to promote effective antiviral immune responses, they can also pave the way to viral dissemination within tissues. Here, we review how recent preclinical findings focusing on the interplay between Siglecs and viruses may translate into promising broad-spectrum therapeutic interventions or key biomarkers to monitor the course of viral infections.

Autoimmune diseases affect tens of millions of people just in the United States alone. Most of the available treatment options are aimed at reducing symptoms but do not lead to cures. Individuals affected with autoimmune diseases suffer from the imbalance between tolerogenic and immunogenic functions of their immune system. Often pathogenesis is mediated by autoreactive B and T cells that escape central tolerance and react against self-antigens attacking healthy tissues in the body.

In recent years Siglecs, sialic-acid-binding immunoglobulin (Ig)-like lectins, have gained attention as immune checkpoints for therapeutic interventions to dampen excessive immune responses and to restore immune tolerance in autoimmune diseases. Many Siglecs function as inhibitory receptors suppressing activation signals in various immune cells through binding to sialic acid ligands as signatures of self.

In this review, we highlight potential of Siglecs in suppressing immune responses causing autoimmune diseases. In particular, we cover the roles of CD22 and Siglec-G/Siglec-10 in regulating autoreactive B cell responses. We discuss several functions of Siglec-10 in the immune modulation of other immune cells, and the potential of therapeutic strategies for restoring immune tolerance by targeting Siglecs and expanding regulatory T cells. Finally, we briefly review efforts evaluating Siglec-based biomarkers to monitor autoimmune diseases.

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial signatures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection.

This article describes why the safety and efficacy assessment of non-nutrient bioactives for reducing chronic disease risk is so complicated, especially for dietary supplements and traditional medicines. Scientists, regulators, and the public have different and sometimes opposing perspectives about bioactives. Drug, food, and traditional medicine models used for bioactive safety assessment are based on different assumptions and use different processes. Efficacy assessment is seldom based on clinical trials of boactives’ effects in reducing chronic disease risk. It usually consists of application of quality assurance measures and evaluation of label claims and commercial speech about ingredients or products to ensure conformity to regulations. Harmonization of safety and efficacy assessment on a global basis is difficult because of differences within and between regulatory systems. The recommendations provided may open the way for bioactives to play a larger health role in the future, fill gaps in data needed for crafting authoritative dietary guidance on intakes, and speed harmonization of global standards.

Anthocyanins (AC) are flavonoids abundant in the human diet, which consumption has been associated to several health benefits, including the mitigation of cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, and neurological disorders. It is widely recognized that the gastrointestinal (GI) tract is not only central for food digestion but actively participates in the regulation of whole body physiology. Given that AC, and their metabolites reach high concentrations in the intestinal lumen after food consumption, their biological actions at the GI tract can in part explain their proposed local and systemic health benefits. In terms of mechanisms of action, AC have been found to: i) inhibit GI luminal enzymes that participate in the absorption of lipids and carbohydrates; ii) preserve intestinal barrier integrity and prevent endotoxemia, inflammation and oxidative stress; iii) sustain goblet cell number, immunological functions, and mucus production; iv) promote a healthy microbiota; v) be metabolized by the microbiota to AC metabolites which will be absorbed and have systemic effects; and vi) modulate the metabolism of GI-generated hormones. This review will summarize and discuss the latest information on AC actions at the GI tract and their relationship to overall health benefits.

This systematic review summarizes findings from human studies investigating the different routes of absorption, metabolism, distribution and excretion (ADME) of dietary flavan-3-ols and their circulating metabolites in healthy subjects. Literature searches were performed in PubMed, Scopus and the Web of Science. Human intervention studies using single and/or multiple intake of flavan-3-ols from food, extracts, and pure compounds were included. Forty-nine human intervention studies met inclusion criteria. Up to 180 metabolites were quantified from blood and urine samples following intake of flavan-3-ols, mainly as phase 2 conjugates of microbial catabolites (n = 97), with phenyl-γ-valerolactones being the most representative ones (n = 34). Phase 2 conjugates of monomers and phenyl-γ-valerolactones, the main compounds in both plasma and urine, reached two peak plasma concentrations (C_max) of 260 and 88 nmol/L at 1.8 and 5.3 h (T_max) after flavan-3-ol intake. They contributed to the bioavailability of flavan-3-ols for over 20%. Mean bioavailability for flavan-3-ols was moderate (31 ± 23%, n bioavailability values = 20), and it seems to be scarcely affected by the amount of ingested compounds. While intra- and inter-source differences in flavan-3-ol bioavailability emerged, mean flavan-3-ol bioavailability was 82% (n = 1) and 63% (n = 2) after (−)-epicatechin and nut (hazelnuts, almonds) intake, respectively, followed by 25% after consumption of tea (n = 7), cocoa (n = 5), apples (n = 3) and grape (n = 2). This highlights the need to better clarify the metabolic yield with which monomer flavan-3-ols and proanthocyanidins are metabolized in humans. This work clarified in a comprehensive way for the first time the ADME of a (poly)phenol family, highlighting the pool of circulating compounds that might be determinants of the putative beneficial effects linked to flavan-3-ol intake. Lastly, methodological inputs for implementing well-designed human and experimental model studies were provided.

Dietary (poly)phenols have been extensively studied for their vasculoprotective effects and consequently their role in preventing or delaying onsets of cardiovascular and metabolic diseases. Even though early studies have ascribed the vasculoprotective properties of (poly)phenols primarily on their putative free radical scavenging properties, recent data indicate that in biological systems, (poly)phenols act primarily through genomic and epigenomic mechanisms. The molecular mechanisms underlying their health properties are still not well identified, mainly due to the use of physiologically non-relevant conditions (native molecules or extracts at high concentrations, rather than circulating metabolites), but also due to the use of targeted genomic approaches aiming to evaluate the effect only on few specific genes, thus preventing to decipher detailed molecular mechanisms involved. The use of state-of-the-art untargeted analytical methods represents a significant breakthrough in nutrigenomics, as these methods enable detailed insights into the effects at each specific omics level. Moreover, the implementation of multi-omics approaches allows integration of different levels of regulation of cellular functions, to obtain a comprehensive picture of the molecular mechanisms of action of (poly)phenols. In combination with bioinformatics and the methods of machine learning, multi-omics has potential to make a huge contribution to the nutrition science. The aim of this review is to provide an overview of the use of the omics, multi-omics, and integrative approaches in studying the vasculoprotective properties of dietary (poly)phenols and address the potentials for use of the machine learning in nutrigenomics.

Considerable evidence has established the importance of specific nutrients that have been found vital for the developing brain. We hypothesize that in a similar manner there should be nutrients vital to the aging brain and that based on aging's distinct pathophysiology they should be different than those essential to development. Specific brain networks that govern cognition are particularly vulnerable to the aging process, resulting in what is referred to as ‘cognitive aging’. Common late-life disorders, however, such as Alzheimer's disease also target these same brain networks. Studies have disambiguated cognitive aging from late-life disease by isolating regions and biological pathways within each network differentially linked to one or the other. This anatomical biology anchors a framework to identify nutrients and/or dietary bioactives relevant to cognitive aging whose utility is illustrated via a decades-long research program into how dietary bioactive flavanols benefit the brain. As we are living longer in cognitively more demanding lives, the framework's ultimate goal is to generate specific dietary recommendations that will fortify our mind for its golden years.