The widespread application of next-generation sequencing technologies has revolutionized microbiome research by enabling high-throughput profiling of the genetic contents of microbial communities. ...How to analyze the resulting large complex datasets remains a key challenge in current microbiome studies. Over the past decade, powerful computational pipelines and robust protocols have been established to enable efficient raw data processing and annotation. The focus has shifted toward downstream statistical analysis and functional interpretation. Here, we introduce MicrobiomeAnalyst, a user-friendly tool that integrates recent progress in statistics and visualization techniques, coupled with novel knowledge bases, to enable comprehensive analysis of common data outputs produced from microbiome studies. MicrobiomeAnalyst contains four modules - the Marker Data Profiling module offers various options for community profiling, comparative analysis and functional prediction based on 16S rRNA marker gene data; the Shotgun Data Profiling module supports exploratory data analysis, functional profiling and metabolic network visualization of shotgun metagenomics or metatranscriptomics data; the Taxon Set Enrichment Analysis module helps interpret taxonomic signatures via enrichment analysis against >300 taxon sets manually curated from literature and public databases; finally, the Projection with Public Data module allows users to visually explore their data with a public reference data for pattern discovery and biological insights. MicrobiomeAnalyst is freely available at http://www.microbiomeanalyst.ca.
Cellular Ca(2+) homeostasis is maintained through the integrated and coordinated function of Ca(2+) transport molecules, Ca(2+) buffers and sensors. These molecules are associated with the plasma ...membrane and different cellular compartments, such as the cytoplasm, nucleus, mitochondria, and cellular reticular network, including the endoplasmic reticulum (ER) to control free and bound Ca(2+) levels in all parts of the cell. Loss of nutrients/energy leads to the loss of cellular homeostasis and disruption of Ca(2+) signaling in both the reticular network and cytoplasmic compartments. As an integral part of cellular physiology and pathology, this leads to activation of ER stress coping responses, such as the unfolded protein response (UPR), and mobilization of pathways to regain ER homeostasis.
Cellular homeostasis is essential for healthy functioning of cells and tissues as well as proper organ development and maintenance. A disruption in cellular homeostasis triggers stress responses ...including the unfolded protein response (UPR), an endoplasmic reticulum (ER) stress coping response. There is increasing evidence that Ca
signaling plays a pivotal role in stress responses, as Ca
is involved many cellular activities. The ER is the main Ca
storage organelle and the source of Ca
for intracellular signaling. The ER is equipped with a variety of stress sensors and contains many Ca
handling proteins that support a role for Ca
in stress sensing and in coordinating strategies required to cope with cellular stress. Maintenance of ER Ca
homeostasis is therefore vital in sustaining cellular functions especially during times of cellular stress. Here we focus on selected aspects of ER Ca
homeostasis, its links to ER stress, and activation of the ER stress coping response.
Fatty acid binding proteins (Fabps) are small soluble proteins that are abundant in the cytosol. These proteins are known to bind a myriad of small hydrophobic molecules and have been postulated to ...serve a variety of roles, yet their precise functions have remained an enigma over half a century of study. Here, we consider recent findings, along with the cumulative findings contributed by many laboratories working on Fabps over the last half century, to synthesize a new outlook for what functions Fabps serve in cells and organisms. Collectively, the findings illustrate that Fabps function as versatile multi‐purpose devices serving as sensors, conveyors and modulators to enable cells to detect and handle a specific class of metabolites, and to adjust their metabolic capacity and efficiency.
Cellular Ca2+ homeostasis is maintained through the integrated and coordinated function of Ca2+ transport molecules, Ca2+ buffers and sensors. These molecules are associated with the plasma membrane ...and different cellular compartments, such as the cytoplasm, nucleus, mitochondria, and cellular reticular network, including the endoplasmic reticulum (ER) to control free and bound Ca2+ levels in all parts of the cell. Loss of nutrients/energy leads to the loss of cellular homeostasis and disruption of Ca2+ signaling in both the reticular network and cytoplasmic compartments. As an integral part of cellular physiology and pathology, this leads to activation of ER stress coping responses, such as the unfolded protein response (UPR), and mobilization of pathways to regain ER homeostasis.
•Ca2+ homeostasis is a highly integrated process controlled by calcium buffers, sensors, channels, exchangers and pumps.•ER stress coping response results in unfolded protein response (UPR).•Disturbed Ca2+ homeostasis/chronic ER stress lead to pathological situations.
The endoplasmic reticulum (ER) is a multifunctional intracellular organelle, a component of the cellular reticular network that allows cells to adjust to a wide variety of conditions. The ...cardiomyocyte reticular network is the ideal location of sensors for both intrinsic and extrinsic factors that disrupt energy and/or nutrient homeostasis and lead to ER stress, a disturbance in ER function. ER stress has been linked to both physiological and pathological states in the cardiovascular system; such states include myocardial infarction, oxygen starvation (hypoxia) and fuel starvation, ischemia, pressure overload, dilated cardiomyopathy, hypertrophy, and heart failure. The ER stress coping response (e.g., the unfolded protein response) is composed of discrete pathways that are controlled by a collection of common regulatory components that may function as a single entity involved in reacting to ER stress. These corrective strategies allow the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. Therefore, the identities of the ER stress corrective strategies are important targets for the development of therapeutic approaches for cardiovascular and other acquired disorders.
Nutrition transition, which includes a change from consumption of traditional to modern diets that feature high-energy density and low nutrient diversity, is associated with acquired metabolic ...syndromes. The human diet is comprised of diverse components which include both nutrients, supplying the raw materials that drive multiple metabolic processes in every cell of the body, and non-nutrients. These components and their metabolites can also regulate gene expression and cellular function via a variety of mechanisms. Some of these components are beneficial while others have toxic effects. Studies have found that persistent disturbance of nutrient metabolism and/or energy homeostasis, caused by either nutrient deficiency or excess, induces cellular stress leading to metabolic dysregulation and tissue damage, and eventually to development of acquired metabolic syndromes. It is now evident that metabolism is influenced by extrinsic factors (
, food, xenobiotics, environment), intrinsic factors (
, sex, age, gene variations) as well as host/microbiota interaction, that together modify the risk for developing various acquired metabolic diseases. It is also becoming apparent that intake of diets with low-energy density but high in nutrient diversity may be the key to promoting and maintaining optimal health.
Bile acids have emerged as important biological molecules that support the solubilization of various lipids and lipid-soluble compounds in the gut, and the regulation of gene expression and cellular ...function. Bile acids are synthesized from cholesterol in the liver and eventually released into the small intestine. The majority of bile acids are recovered in the distal end of the small intestine and then returned to the liver for reuse. The components of the mechanism responsible for the recycling of bile acids within the enterohepatic circulation have been identified whereas the mechanism for intracellular transport is less understood. Recently, the ileal lipid binding protein (ILBP; human gene symbol FABP6) was shown to be needed for the efficient transport of bile acids from the apical side to the basolateral side of enterocytes in the distal intestine. This review presents an overview of the transport of bile acids between the liver and the gut as well as within hepatocytes and enterocytes. A variety of pathologies is associated with the malfunction of the bile acid transport system.
The endoplasmic reticulum (ER) is a multifunctional intracellular organelle supporting many processes required by virtually every mammalian cell, including cardiomyocytes. It performs diverse ...functions, including protein synthesis, translocation across the membrane, integration into the membrane, folding, posttranslational modification including N-linked glycosylation, and synthesis of phospholipids and steroids on the cytoplasmic side of the ER membrane, and regulation of Ca(2+) homeostasis. Perturbation of ER-associated functions results in ER stress via the activation of complex cytoplasmic and nuclear signaling pathways, collectively termed the unfolded protein response (UPR) (also known as misfolded protein response), leading to upregulation of expression of ER resident chaperones, inhibition of protein synthesis and activation of protein degradation. The UPR has been associated with numerous human pathologies, and it may play an important role in the pathophysiology of the heart. ER stress responses, ER Ca(2+) buffering, and protein and lipid turnover impact many cardiac functions, including energy metabolism, cardiogenesis, ischemic/reperfusion, cardiomyopathies, and heart failure. ER proteins and ER stress-associated pathways may play a role in the development of novel UPR-targeted therapies for cardiovascular diseases.
Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a ...clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR) pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function.
We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER) homeostasis, transient activation of the unfolded protein response (UPR) pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA) is sufficient to prevent cardiac fibrosis, and improved exercise tolerance.
We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.
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