Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know

Sepsis is a syndrome caused by a deregulated host response to infection, representing the primary cause of death from infection. In animal models, the mortality rate is strongly dependent on the time of sepsis induction, suggesting a main role of the circadian system. In patients undergoing sepsis, deregulated circadian rhythms have also been reported. Here we review data related to the timing of sepsis induction to further understand the different outcomes observed both in patients and in animal models. The magnitude of immune activation as well as the hypothermic response correlated with the time of the worst prognosis. The different outcomes seem to be dependent on the expression of the clock gene Bmal1 in the liver and in myeloid immune cells. The understanding of the role of the circadian system in sepsis pathology could be an important tool to improve patient therapies.

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REVIEW OF RESEARCH ON THE RELATIONSHIP BETWEEN CIRCADIAN RHYTHMS AND CARCINOGENESIS USING ANIMAL MODELS

Siberian Journal of Oncology ◽

10.21294/1814-4861-2021-20-3-134-143 ◽

2021 ◽

Vol 20 (3) ◽

pp. 134-143

Author(s):

G. S. Kireeva ◽

E. A. Gubareva ◽

M. A. Maydin ◽

A. V. Panchenko ◽

M. L. Tyndyk ◽

...

Keyword(s):

Circadian Rhythms ◽

Animal Models ◽

Clock Gene ◽

Clock Genes ◽

Tumor Development ◽

Malignant Neoplasms ◽

Light Cycle ◽

Gene System ◽

The Relationship

Purpose of the study: to review in vivo studies on the relationship and role of various molecular genetic components of the circadian rhythm system in the initiation and development of malignant neoplasms. in contrast to clinical and epidemiological studies, animal models, including transgenic animal models, can model various changes and disturbances in the activity of clock genes and track the results of these changes.Material and Methods. the review includes data from studies carried out over the past 10 years in animal models, studying the mechanisms and effects of disturbances in the system of circadian rhythms related to the formation and development of tumors. the data sources for the review were the Medline, embase and scopus databases.Results. analysis of the literature has shown that interference with the work of the «biological clock» by changing the light cycle, disrupting the expression of clock genes and other manipulations is a factor predisposing to the development of tumors. in tumors of various types, the expression of clock genes is often mismatched, and it is unclear at what stage of their formation this occurs. in addition, the development of tumors disrupts the circadian homeostasis of the body. there are three key areas of research aimed at studying the role of circadian rhythms in tumor development: disturbance of circadian rhythms as a carcinogenic factor, disturbances in the clock gene system in a tumor, disturbances in the clock gene system of the whole organism, provoked by tumor development.Conclusion. the results of studies on animal models demonstrate that the relationship between the disturbance of circadian rhythms and the tumor process is complex since the causal relationship has not yet been studied. in this regard, the prospect of targeted pharmacological correction of circadian rhythms in clinical practice in cancer patients does not seem to be the nearest one.

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Mast cells are necessary for the hypothermic response to LPS-induced sepsis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90888.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. R595-R602 ◽

Cited By ~ 23

Author(s):

Katherine M. Nautiyal ◽

Heather McKellar ◽

Ann-Judith Silverman ◽

Rae Silver

Keyword(s):

Mast Cells ◽

Low Frequency ◽

High Dose ◽

Brain Site ◽

Hypothermic Response ◽

Tnf Α ◽

Sepsis Induction ◽

Baseline Temperature ◽

Ifn Γ

As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural “cross talk.” Using mast cell-deficient KitW-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). KitW-sh/W-sh and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (Tc) of WT mice decreased by ∼3°C, whereas KitW-sh/W-sh mice did not become hypothermic but instead exhibited pronounced low-frequency Tc oscillations around their baseline temperature. In addition, KitW-sh/W-sh mice had lower levels of whole brain TNF-α but no differences in IL-1β, IL-6, IFN-γ, or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF-α in sepsis. KitW-sh/W-sh mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, KitW-sh/W-sh and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF-α (1.5 μg icv), reduced nighttime Tc and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 μg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.

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Flies, clocks and evolution

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0961 ◽

2001 ◽

Vol 356 (1415) ◽

pp. 1769-1778 ◽

Cited By ~ 29

Author(s):

Ezio Rosato ◽

Charalambos P. Kyriacou

Keyword(s):

Gene Regulation ◽

Negative Feedback ◽

Clock Gene ◽

Circadian System ◽

Gene Duplications ◽

Closely Related Species ◽

Feedback Model ◽

Silk Moth ◽

The Brain

The negative feedback model for gene regulation of the circadian mechanism is described for the fruitfly, Drosophila melanogaster . The conservation of function of clock molecules is illustrated by comparison with the mammalian circadian system, and the apparent swapping of roles between various canonical clock gene components is highlighted. The role of clock gene duplications and divergence of function is introduced via the timeless gene. The impressive similarities in clock gene regulation between flies and mammals could suggest that variation between more closely related species within insects might be minimal. However, this is not borne out because the expression of clock molecules in the brain of the giant silk moth, Antheraea pernyi , is not easy to reconcile with the negative feedback roles of the period and timeless genes. Variation in clock gene sequences between and within fly species is examined and the role of co-evolution between and within clock molecules is described, particularly with reference to adaptive functions of the circadian phenotype.

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Role of the saturated fatty acid palmitate in the interconnected hypothalamic control of energy homeostasis and biological rhythms

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00433.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E133-E140 ◽

Cited By ~ 6

Author(s):

Erika K. Tse ◽

Ashkan Salehi ◽

Matthew N. Clemenzi ◽

Denise D. Belsham

Keyword(s):

Circadian Rhythms ◽

Cell Lines ◽

High Fat Diet ◽

Energy Homeostasis ◽

Clock Gene ◽

Neuronal Cell ◽

Whole Body ◽

High Fat ◽

Neuronal Cell Lines

The brain, specifically the hypothalamus, controls whole body energy and glucose homeostasis through neurons that synthesize specific neuropeptides, whereas hypothalamic dysfunction is linked directly to insulin resistance, obesity, and type 2 diabetes mellitus. Nutrient excess, through overconsumption of a Western or high-fat diet, exposes the hypothalamus to high levels of free fatty acids, which induces neuroinflammation, endoplasmic reticulum stress, and dysregulation of neuropeptide synthesis. Furthermore, exposure to a high-fat diet also disrupts normal circadian rhythms, and conversely, clock gene knockout models have symptoms of metabolic disorders. While whole brain/animal studies have provided phenotypic end points and important clues to the genes involved, there are still major gaps in our understanding of the intracellular pathways and neuron-specific components that ultimately control circadian rhythms and energy homeostasis. Because of its complexity and heterogeneous nature, containing a diverse mix cell types, it is difficult to dissect the critical hypothalamic components involved in these processes. Of significance, we have the capacity to study these individual components using an extensive collection of both embryonic- and adult-derived, immortalized hypothalamic neuronal cell lines from rodents. These defined neuronal cell lines have been used to examine the impact of nutrient excess, such as palmitate, on circadian rhythms and neuroendocrine signaling pathways, as well as changes in vital neuropeptides, leading to the development of neuronal inflammation; the role of proinflammatory molecules in this process; and ultimately, restoration of normal signaling, clock gene expression, and neuropeptide synthesis in disrupted states by beneficial anti-inflammatory compounds in defined hypothalamic neurons.

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Estradiol regulates daily rhythms underlying diet-induced obesity in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00365.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E1172-E1181 ◽

Cited By ~ 1

Author(s):

Oluwabukola Omotola ◽

Sandra Legan ◽

Emily Slade ◽

Ayooluwatomiwa Adekunle ◽

Julie S. Pendergast

Keyword(s):

Circadian Rhythms ◽

Eating Behavior ◽

High Fat Diet ◽

Circadian System ◽

High Fat ◽

Daily Rhythms ◽

Diet Induced Obesity ◽

Ovariectomized Mice ◽

Circulating Levels

The circadian system is a critical regulator of metabolism and obesity in males, but its role in regulating obesity in females is poorly understood. Because there are sex differences in the development of obesity and susceptibility to obesity-related disorders, we sought to determine the role of estrogens in regulating the circadian mechanisms underlying diet-induced obesity. When fed high-fat diet, C57BL/6J male mice gain weight, whereas females are resistant to diet-induced obesity. Here, we demonstrate that estradiol regulates circadian rhythms in females to confer resistance to diet-induced obesity. We found that ovariectomized females with undetectable circulating estrogens became obese and had disrupted daily rhythms of eating behavior and locomotor activity when fed a high-fat diet. The phase of the liver molecular circadian rhythm was also altered by high-fat diet feeding in ovariectomized mice. Estradiol replacement in ovariectomized females a fed high-fat diet rescued these behavioral and tissue rhythms. Additionally, restoring the daily rhythm of eating behavior in ovariectomized females with time-restricted feeding inhibited diet-induced obesity and insulin resistance. Together, these data suggest that the circadian system is a target for treating obesity and its comorbidities in women after menopause, when circulating levels of estrogens are too low to protect their circadian rhythms.

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Role of non-neural signals in regulation of circadian rhythms of core clock gene expression in mouse peripheral organs

Frontiers in Neuroendocrinology ◽

10.1016/j.yfrne.2006.03.040 ◽

2006 ◽

Vol 27 (1) ◽

pp. 18-19

Author(s):

Eric L. Bittman ◽

Anastasia Nikiforov ◽

Ruth Harris ◽

Judy McKinley Brewer

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Clock Gene ◽

Neural Signals ◽

Peripheral Organs ◽

Clock Gene Expression ◽

Core Clock Gene

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Role of spectrin in membrane fusion and in shape change of human erythrocyte ghost

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100082509 ◽

1978 ◽

Vol 36 (2) ◽

pp. 328-329

Author(s):

Hideo Hayashi ◽

Yoshikazu Hirai ◽

John T. Penniston

Keyword(s):

Conformational Changes ◽

Human Erythrocyte ◽

Shape Change ◽

Membrane Surface ◽

Slight Modification ◽

Active Role ◽

Main Role ◽

Bank Blood ◽

Human Erythrocyte Ghost

Spectrin is a membrane associated protein most of which properties have been tentatively elucidated. A main role of the protein has been assumed to give a supporting structure to inside of the membrane. As reported previously, however, the isolated spectrin molecule underwent self assemble to form such as fibrous, meshwork, dispersed or aggregated arrangements depending upon the buffer suspended and was suggested to play an active role in the membrane conformational changes. In this study, the role of spectrin and actin was examined in terms of the molecular arrangements on the erythrocyte membrane surface with correlation to the functional states of the ghosts.Human erythrocyte ghosts were prepared from either freshly drawn or stocked bank blood by the method of Dodge et al with a slight modification as described before. Anti-spectrin antibody was raised against rabbit by injection of purified spectrin and partially purified.

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Mesophyll conductance: the leaf corridors for photosynthesis

Biochemical Society Transactions ◽

10.1042/bst20190312 ◽

2020 ◽

Vol 48 (2) ◽

pp. 429-439 ◽

Cited By ~ 3

Author(s):

Jorge Gago ◽

Danilo M. Daloso ◽

Marc Carriquí ◽

Miquel Nadal ◽

Melanie Morales ◽

...

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Main Role ◽

Mesophyll Conductance ◽

Future Studies ◽

Cell Structures ◽

Leaf Tissues ◽

Change Framework ◽

Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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