ER Stress, Human Health and Role of Ca2+-Binding Chaperones

Nutraceuticals have been around for quite some time. As the nomenclature suggests, they are placed somewhere between food (nutra-) and medicine (-ceuticals) in terms of their impact on human health. Researches have focused on the impact of various types of nutraceuticals on health, their efficacy in health promotion and disease prevention, and often on suitable uses of certain categories of nutraceuticals for specific health issues. However, we are still far from utilizing the immense potential of nutraceuticals for benefiting human health in a substantial manner. We review the available scholarly literature regarding the role of nutraceuticals in health promotion, their efficacy in disease prevention and the perception of nutraceuticals' health benefits by consumers. Thereafter we analyze the need for regulation of nutraceuticals and various provisions regarding the same.

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Guild-based analysis for understanding gut microbiome in human health and diseases

Genome Medicine ◽

10.1186/s13073-021-00840-y ◽

2021 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Guojun Wu ◽

Naisi Zhao ◽

Chenhong Zhang ◽

Yan Y. Lam ◽

Liping Zhao

Keyword(s):

Gut Microbiota ◽

Human Health ◽

Gut Microbiome ◽

Association Studies ◽

Causative Role ◽

Disease Phenotypes ◽

Genetic Complexity ◽

Causative Agents ◽

Specific Health

AbstractTo demonstrate the causative role of gut microbiome in human health and diseases, we first need to identify, via next-generation sequencing, potentially important functional members associated with specific health outcomes and disease phenotypes. However, due to the strain-level genetic complexity of the gut microbiota, microbiome datasets are highly dimensional and highly sparse in nature, making it challenging to identify putative causative agents of a particular disease phenotype. Members of an ecosystem seldomly live independently from each other. Instead, they develop local interactions and form inter-member organizations to influence the ecosystem’s higher-level patterns and functions. In the ecological study of macro-organisms, members are defined as belonging to the same “guild” if they exploit the same class of resources in a similar way or work together as a coherent functional group. Translating the concept of “guild” to the study of gut microbiota, we redefine guild as a group of bacteria that show consistent co-abundant behavior and likely to work together to contribute to the same ecological function. In this opinion article, we discuss how to use guilds as the aggregation unit to reduce dimensionality and sparsity in microbiome-wide association studies for identifying candidate gut bacteria that may causatively contribute to human health and diseases.

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Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

International Journal of Molecular Sciences ◽

10.3390/ijms22052567 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2567

Author(s):

Yann S. Gallot ◽

Kyle R. Bohnert

Keyword(s):

Skeletal Muscle ◽

Er Stress ◽

Unfolded Protein Response ◽

Smooth Endoplasmic Reticulum ◽

Skeletal Muscle Atrophy ◽

Unfolded Protein ◽

The Individual ◽

The Unfolded Protein Response ◽

Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

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Liquid–liquid phase separation in human health and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00678-1 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Bin Wang ◽

Lei Zhang ◽

Tong Dai ◽

Ziran Qin ◽

Huasong Lu ◽

...

Keyword(s):

Phase Separation ◽

Liquid Phase ◽

Human Health ◽

Essential Role ◽

Current Knowledge ◽

Vital Role ◽

Liquid Phase Separation ◽

Eukaryotic Cells ◽

Liquid Liquid Phase Separation

AbstractEmerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy—but is fast-growing—it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

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Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽

10.1007/s00125-021-05488-2 ◽

2021 ◽

Author(s):

Yukina Takeichi ◽

Takashi Miyazawa ◽

Shohei Sakamoto ◽

Yuki Hanada ◽

Lixiang Wang ◽

...

Keyword(s):

Er Stress ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Primary Hepatocytes ◽

Alcoholic Fatty Liver ◽

Expression Of Genes ◽

Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

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Activation of ER stress and apoptosis by α- and β-zearalenol in HCT116 cells, protective role of Quercetin

NeuroToxicology ◽

10.1016/j.neuro.2015.11.004 ◽

2016 ◽

Vol 53 ◽

pp. 334-342 ◽

Cited By ~ 19

Author(s):

Intidhar Ben Salem ◽

Alexandre Prola ◽

Manel Boussabbeh ◽

Arnaud Guilbert ◽

Hassen Bacha ◽

...

Keyword(s):

Er Stress ◽

Protective Role ◽

Hct116 Cells

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c-Jun Inhibits Thapsigargin-Induced ER Stress Through Up-Regulation of DSCR1/Adapt78

Experimental Biology and Medicine ◽

10.3181/0803-rm-84 ◽

2008 ◽

Vol 233 (10) ◽

pp. 1289-1300 ◽

Cited By ~ 25

Author(s):

Peng Zhao ◽

Xiaoyan Xiao ◽

Agnes S. Kim ◽

M. Fatima Leite ◽

Jinxia Xu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Wild Type Mouse ◽

Mouse Fibroblast ◽

Expression Levels ◽

Mouse Fibroblasts ◽

The Unfolded Protein Response ◽

Calcineurin Activity

The endoplasmic reticulum (ER) is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed “ER stress”, can perturb ER function, leading to the activation of a complex response known as the unfolded protein response (UPR). Although c-Jun N-terminal kinase (JNK) activation is nearly always associated with cell death by various stimuli, the functional role of JNK in ER stress-induced cell death remains unclear. JNK regulates gene expression through the phosphorylation and activation of transcription factors, such as c-Jun. Here, we investigated the role of c-Jun in the regulation of ER stress-related genes. c-Jun expression levels determined the response of mouse fibroblasts to ER stress induced by thapsigargin (TG, an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase). c-jun−/− mouse fibroblast cells were more sensitive to TG-induced cell death compared to wild-type mouse fibroblasts, while reconstitution of c-Jun expression in c-jun−/− cells (c-Jun Re) enhanced resistance to TG-induced cell death. The expression levels of ER chaperones Grp78 and Gadd153 induced by TG were lower in c-Jun Re than in c-jun−/− cells. Moreover, TG treatment significantly increased calcineurin activity in c-jun−/− cells, but not in c-Jun Re cells. In c-Jun Re cells, TG induced the expression of Adapt78, also known as the Down syndrome critical region 1 (DSCR1), which is known to block calcineurin activity. Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.

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N-Acetylcysteine (NAC): Impacts on Human Health

Antioxidants ◽

10.3390/antiox10060967 ◽

2021 ◽

Vol 10 (6) ◽

pp. 967

Author(s):

Micaely Cristina dos Santos Tenório ◽

Nayara Gomes Graciliano ◽

Fabiana Andréa Moura ◽

Alane Cabral Menezes de Oliveira ◽

Marília Oliveira Fonseca Goulart

Keyword(s):

Human Health ◽

Therapeutic Potential ◽

Experimental Studies ◽

Primary Role ◽

Necrosis Factor Alpha ◽

Biochemical Basis ◽

Tnf Α ◽

Factor Alpha ◽

Anti Inflammatory

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC’s relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.

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