The Tilapia collagen peptide mixture TY001 protects against LPS-induced inflammation,disruption of glucose metabolism,and aberrant expression of circadian clock genes in mice

The Tilapia collagen peptide mixture TY001 has been shown to accelerate wound healing in streptozotocin-induced diabetic mice and to protect against streptozotocin-induced inflammation and elevation in blood glucose. The goals of the present study are to further study TY001 effects on lipopolysaccharide (LPS)-induced inflammation and metabolic syndrome. LPS is known to disrupt circadian clock to produce toxic effects, the effects of TY001 on rhythmic alterations of serum cytokines and hepatic clock gene expressions were examined. Mice were given TY001 (30 g/L, ≈ 40 g/kg) through the drinking water for 30 days, and on the 21^st day of TY001 supplementation, LPS (0.25 mg/kg, ip, daily) was given for 9 days to establish the inflammation model. Repeated LPS injections produced inflammation, impaired glucose metabolism, and suppressed the expression of circadian clock core genes Bmal1 and Clock; clock feedback gene Cry1, Cry2, Per1, and Per2; clock target gene Rev-erbα and RORα. TY001 prevented LPS-induced elevations of TNFα, IL-1β, IL-6, and IL-10 in the liver, along with improved histopathology. TY001 reduced LPS-elevated fasting blood glucose and increased LPS-reduced serum insulin levels, probably via increased glucose transporter GLUT2, enhanced insulin signaling p-Akt and p-IRS-1^Try612. Importantly, LPS-induced circadian elevations of serum TNFα and IL-1β and aberrant expression of circadian clock genes in the liver were ameliorated by TY001. Immunohistochemistry revealed that the LPS decreased Bmal1 and Clock protein in the liver, which was recovered by TY001. Taken together, TY001 is effective against LPS-induced inflammation, disruption of glucose metabolism and disruption of circadian clock gene expressions.

Abbreviations: TY001: Tilapia collagen peptide mixture; LPS: Lipopolysaccharide; TNFα: Tumor necrosis factor-α; IL-1β: Interleukin-1β; GLUT2: Glucose transporter 2     

Effects of altered photoperiod on circadian clock and lipid metabolism in rats

Disruption of circadian clock timekeeping due to changes in the photoperiod enhances the risk of lipid metabolism disorders and metabolic syndrome. However, the effects of altered photoperiods on the circadian clock and lipid metabolism are not well understood. To explore the effects of altered photoperiods, we developed a rat model where rats were exposed to either short-day or long-day conditions. Our findings demonstrated that altered photoperiods mediated circadian clocks by partly disrupting rhythmicity and shifting phase values of clock genes. We also showed that compared to long-day conditions, rats under short-day conditions exhibited more photoperiodic changes in a variety of physiological outputs related to lipid metabolism, such as significant increases in serum triglyceride (TG), high-density lipoprotein, and leptin levels, as well as increased body weight, fat:weight ratio, and hepatic TG levels. These increments were gained possibly through upregulated expression of forkhead box O1 (FoxO1), which partly mediates the expression of peroxisome proliferator-activated receptorα (PPARα) to increase the expression of phosphoenolpyruvate carboxykinase (PEPCK), peroxisome proliferator-activated receptor-g coactivator-1β (PGC1β), and fatty acid synthase (Fasn). In addition, the oscillation rhythms of FoxO1, PEPCK, PGC1β, and Fasn expression levels in the livers of rats exposed to a short-day photoperiod were more robust than those exposed to a long-day photoperiod. These findings suggest that a change in photoperiod can partly disrupt the circadian rhythmcity of clock genes, impair lipid metabolism, and promote obesity.     

哺乳动物生物钟与能量代谢的相关研究进展

生物钟广泛存在于各种生物体中,是生命体的一种内源调节机制。哺乳动物生物钟系统与机体营养代谢和能量平衡有着密切的关系。概述了生物钟系统通过营养途径、限速酶途径、核受体途径对哺乳动物机体代谢活动和能量平衡的调控,以及哺乳动物代谢稳态对生物钟系统的影响,从而为从生物钟调控的角度治疗和防控代谢综合征提供新的思路。     

Crosstalk between xenobiotics metabolism and circadian clock

Many aspects of physiology and behavior in organisms from bacteria to man are subjected to circadian regulation. Indeed, the major function of the circadian clock consists in the adaptation of physiology to daily environmental change and the accompanying stresses such as exposition to UV-light and food-contained toxic compounds. In this way, most aspects of xenobiotic detoxification are subjected to circadian regulation. These phenomena are now considered as the molecular basis for the time-dependence of drug toxicities and efficacy. However, there is now evidences that these toxic compounds can, in turn, regulate circadian gene expression and thus influence circadian rhythms. As food seems to be the major regulator of peripheral clock, the possibility that food-contained toxic compounds participate in the entrainment of the clock will be discussed.     

Mechanisms of hormonal regulation of the peripheral circadian clock in the colon

Colonic function is controlled by an endogenous clock that allows the colon to optimize its function on the daytime basis. For the first time, this study provided evidence that the clock is synchronized by rhythmic hormonal signals. In rat colon, adrenalectomy decreased and repeated applications of dexamethasone selectively rescued circadian rhythm in the expression of the clock gene Per1. Dexamethasone entrained the colonic clock in explants from mPer2^Luc mice in vitro. In contrast, pinealectomy had no effect on the rat colonic clock, and repeated melatonin injections were not able to rescue the clock in animals maintained in constant light. Additionally, melatonin did not entrain the clock in colonic explants from mPer2^Luc mice in vitro. However, melatonin affected rhythmic regulation of Nr1d1 gene expression in vivo. The findings provide novel insight into possible beneficial effects of glucocorticoids in the treatment of digestive tract-related diseases, greatly exceeding their anti-inflammatory action.     

松果体昼夜节律生物钟分子机制的研究进展

在各种非哺乳类脊椎动物中 ,松果体起着中枢昼夜节律振荡器的作用。近来 ,在鸟类松果体中相继发现了几种钟基因 ,如Per、Cry、Clock和Bmal等 ,其表达的时间变化规律与哺乳类视交叉上核 (SCN)的非常相似。钟的振荡由其自身调控反馈环路的转录和翻译组成 ,鸟类松果体和哺乳类SCN似乎具有共同的钟振荡基本分子构架 ;若干钟基因产物作为正向或负向调节子影响钟的振荡 ;昼夜性的控时机制同时也需要翻译后事件的参与。这些过程对钟振荡器的稳定性和 /或钟导引的光输入通路有着重要的调控作用     

Research on circadian clock genes in non-small-cell lung carcinoma

Circadian clock genes have become a hot topic in cancer research in recent years, and more and more studies are showing that clock genes are involved in regulating cell proliferation cycle and apoptosis of malignant tumors, neuroendocrine and immune function, and other processes. Lung cancer is a malignant tumor with increasing incidence worldwide. The pathogenesis of lung cancer is extremely complicated and includes genetic factors, living environment, and smoking, and the occurrence of lung cancer is related to the regulation of many oncogenes and tumor suppressor genes. But there are few studies on clock genes in lung cancer. Studies on clock genes may help to better understand the mechanism of lung cancer development for an improved treatment. The expressions of all 14 kinds of clock genes in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), two main kinds of non-small-cell lung cancer (NSCLC), were studied based on integration and analysis of data from The Cancer Genome Atlas (TCGA) to show the association between clock gene expression and prognosis of cancer patients. Analysis of TCGA data indicated that overexpression of Cry2, BMAL1, and RORA with underexpression of Timeless and NPAS2 was associated with a favorable prognosis of ADC, and the expression of NPAS2 was associated with the time of patient survival. Additionally, the expression of Cry2 was related to TNM stage. In SCC, high expression of DEC1 was correlated with poor overall survival in patients and the expression of Timeless was associated with the time of patient survival. In NSCLC, circadian clock genes constitute cancer circadian rhythm by interacting with each other, showing that asynchrony with normal tissues, which collectively controlling the occurrence and development of NSCLC.     

Effects of iron status on expression of circadian clock genes and serum lipid metabolism in sucking piglets

The aim of the study is to determine the effects of iron on circadian clock gene expression and serum lipid metabolism in sucking piglets. Twenty-four neonatal piglets were selected and randomly assigned into three groups (A, B, and C) with eight replicates. Group A were received 1 mL physiological saline by intramuscular administration at d 3 and d 10; group B were received 1 mL iron dextran (100 mg) by intramuscular administration at d 3 and 1 mL physiological saline at d 10, respectively; group C were received 1 mL of iron dextran (100 mg) by intramuscular administration at both d 3 and d 10. Our results reveal that the relative expressions of Cry1, Cry2, Per1, Per2, and Bmal in liver were significantly different in the three groups (p < 0.05). Meanwhile, the content of triglyceride (TG) and high-density lipoprotein (HDL) in serum were also affected by the iron supplementation (p < 0.05). These results indicated that iron affected hepatic circadian clock genes significantly, meanwhile, it may possible association with lipid metabolism.     

How temperature affects the circadian clock of Neurospora crassa

Light and temperature are major environmental cues that influence circadian clocks. The molecular effects of these zeitgebers on the circadian clock of Neurospora crassa have been studied intensively during the last decade. While signal transduction of light into the circadian clock is quite well characterized, we have only recently begun to understand the molecular mechanisms that underlie temperature sensing. Here we summarize briefly the current knowledge about the effects of temperature on the circadian clock of Neurospora crassa.     

Exploring the role of circadian clock gene and association with cancer pathophysiology

ABSTRACT

Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues.

The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock.

Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body’s internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients.

In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns.     

The regulation of plant growth by the circadian clock

Circadian regulated changes in growth rates have been observed in numerous plants as well as in unicellular and multicellular algae. The circadian clock regulates a multitude of factors that affect growth in plants, such as water and carbon availability and light and hormone signalling pathways. The combination of high-resolution growth rate analyses with mutant and biochemical analysis is helping us elucidate the time-dependent interactions between these factors and discover the molecular mechanisms involved. At the molecular level, growth in plants is modulated through a complex regulatory network, in which the circadian clock acts at multiple levels.     

How temperature affects the circadian clock of Neurospora crassa

Light and temperature are major environmental cues that influence circadian clocks. The molecular effects of these zeitgebers on the circadian clock of Neurospora crassa have been studied intensively during the last decade. While signal transduction of light into the circadian clock is quite well characterized, we have only recently begun to understand the molecular mechanisms that underlie temperature sensing. Here we summarize briefly the current knowledge about the effects of temperature on the circadian clock of Neurospora crassa.     

Light and serotonin phase-shift the circadian clock in the cricket optic lobe in vitro

Light and serotonin were found to cause phase shifts of the circadian neural activity rhythm in the optic lobe of the cricket Gryllus bimaculatus cultured in vitro. The two phase-shifting agents yielded phase-response curves different in shape. Light induced phase delay and advance in the early and late subjective night, respectively, and almost no shifts in the subjective day, whereas serotonin phase-advances the clock during the subjective day and induced delay shifts during the subjective night. The largest phase advance and delay occurred at circadian time 21 and 12, respectively, for light, and circadian time 3 and 18, respectively, for serotonin. Quipazine, a nonspecific serotonin agonist, induced phase advance and phase delay at circadian time 3 and 18, respectively, like serotonin. (±)8-OH-DPAT, a specific 5-HT_1A agonist, phase delayed by 2 h at the subjective night, but produced no significant phase shifts at the subjective day. When NAN-190, a specific 5-HT_1A antagonist, was applied together with quipazine, it completely blocked the phase delay at circadian time 18, whereas it had no effect on the advance shifts induced by quipazine. The results suggest that the phase dependency of serotonin-induced phase shifts of the clock may be partly attributable to the daily change in receptor type. Accepted: 4 July 1999     

Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver

Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.     

Energy-dependent phases of the circadian clock and the clock-controlled leaf movement in Phaseolus coccineus L.

The energy requirements of the various phases of the circadian clock in the laminar pulvini cells of primary leaves of Phaseolus coccineus L. were investigated using 4-h pulses of NaCN (5 mM) and NaN₃ (1 mM). The induced phase shifts were calculated from the timing of the subjective night position during the third cycle after the treatment. Both inhibitors produce advances during phases which are correlated with the upward movement of the leaf (ca. 0–12 h after the maximum of the subjective night position) and during phases which are correlated with the downward movement of the leaf (ca. 20–28 h after the maximum of the subjective night position). Maximal advances are induced during the phase which is correlated with the maximum of the subjective night position (hour 0), whereas during phases which are correlated with the subjective day position (ca. 12–20 h after the maximum of the subjective night position) the inhibitors have no effect or induce only small advances. These results demonstrate that the part of the circadian cycle which, according to Bünning's tension-relaxation model of the circadian clock, is characterized by features of relaxation, represents a sequence of phases with decreasing energy requirement, whereas the tension part of the circadian cycle represents a sequence of phases with increasing energy requirement. The energy requirement for changing and maintaining the leaf positions was investigated by continuously offering NaCN, NaN₃, and dinitrophenol (DNP) to leaves with intact and half (flexor cut away) pulvini. The substances inhibit in both pulvini the upward movement or induce a downward movement, depending on the leaf position, when the transfer to the inhibitor solution takes place. These results give evidence that the movement of intact pulvini reflects the turgor (volume) state of the extensor cells and that the increase of turgor (volume) and high turgor (volume) state requires more energy than the decrease of turgor (volume) or low turgor (small volume) state. Therefore, the time course of the energy requirements of the circadian clock and the clock-controlled turgor (volume states or leaf movement) is out of phase during a circadian cycle. Consequently the reaction of the clock-controlled leaf movement to the reduced energy supply can mask the clock behavior in pulse and step experiments. The phase response curves towards CN^- and N ₃ ^- reflect the time course of the CN^--induced membrane depolarizations (the energy requirement of the electrogenic pump) in extensor cells of the pulvinus (Freudling et al. (1980), Plant Physiol. 65, 966–968), and both are out of phase with the time course of the energy requirement of the turgor. Consequently it is hypothesized that in Phaseolus advances are due to membrane depolarization and that at least in this organism electric properties of the plasmalemma are essentially involved in the mechanism of the circadian clock.Abbreviations LD light-dark cycle - LL continuous light - DNP dinitrophenol This paper is dedicated to Professor Erwin Bünning on the occasion of his 75th birthdayIn this paper zero corresponds to the second maximum of the subjective night position of the leaves after transfer to constant conditions. Zero to twelve hours corresponds approximately to the upward movement of the leaves, 12–20 h to the elevated (subjective day) position, and 20–28 h to the downward movement of the leaves. In other circadian systems Pittendrigh's CT (circadian time) convention is used. CT 00 is the time of dawn after a 12-h light/12-h dark cycle. Since in Phaseolus the plants are raised in a LD cycle different from 12:12 and since the phases at dawn differ considerably from leaf to leaf and are furthermore not precisely determinable (whereas the subjective night position of the leaves is a well-defined and recognizable phase) this convention is not followed in Phaseolus. Phase zero in Phaseolus corresponds to approximately CT 18 in other systems     

Sleep and circadian rhythms: key components in the regulation of energy metabolism

In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are "interacting epidemics." The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease.     

Light-induced phase shifting of the circadian clock in Neurospora crassa requires ammonium salts at high pH

Effects of external ionic conditions on light induced phase shifting of the circadian rhythm of conidiation in Neurospora crassa were examined in simple buffer solutions for discerning effects of individual ions. Mycelia were cultured to liquid media of different pHs and then transferted to 10 mM piperazine-N,N-bis(2-ethanesulmonic acid) (Pipes) buffer of various pHs and irradiated with while light. The phase of the rhythm of dark controls was not changed by transfer from medium to buffer. When mycelia were cultured in media of pH above 6.7, light did not advance the phase of the clock in Pipes buffer alone. However, light-induced phase advance was restored when an ammonium salt was added to buffer of pH higher than 7.6. An amination-defective mutant, bd am, showed the same response to ammonium nitrate as the wild-type strain, bd. Ammonium must be present before light irradiation for restoration of phase shifting. Free-amino-acid pools in the cells were changed by treatment with Pipes buffer: aspartle acid, glutamic acid, ammonia, glutamine and ornithine levels decreased, while lysine and histidine increased. Addition of ammonium nitrate to Pipes buffer resulted in further changes in amino-acid pools; lysine, histidine, arginine, alanine and ornithine decreased, and glutamine levels increased. Irradiation did not result in significant changes in amino acid pools.Abbreviation Pipes piperazine-N,N-bis(2-ethanesulfoniccid)