scholarly journals Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Manhui Zhang ◽  
Kohei Kobayashi ◽  
Haruki Atsumi ◽  
Yuma Katada ◽  
Yusuke Nakane ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Drug Repositioning ◽  
Explant Culture ◽  
Kampo Medicine ◽  
Crude Drug ◽  
Increased Risk ◽  
Crude Drugs ◽  
Underlying Mechanisms

AbstractCircadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, cardiovascular disease, and cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target AKT and its relevant signaling pathways. As expected, analysis of the major ingredients targeting AKT signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of AKT, and triple knockdown of AKT isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption.

scholarly journals The Association between Circadian Clock Gene Polymorphisms and Metabolic Syndrome: A Systematic Review and Meta-Analysis

Biology ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Ivana Škrlec ◽  
Jasminka Talapko ◽  
Snježana Džijan ◽  
Vera Cesar ◽  
Nikolina Lazić ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Circadian Rhythm ◽  
Circadian Clock ◽  
Gene Polymorphisms ◽  
Clock Gene ◽  
Meta Analysis ◽  
Predictive Biomarkers ◽  
Circadian Clock Gene ◽  
Increased Risk ◽  
Research Findings

Metabolic syndrome (MetS) is a combination of cardiovascular risk factors associated with type 2 diabetes, obesity, and cardiovascular diseases. The circadian clock gene polymorphisms are very likely to participate in metabolic syndrome genesis and development. However, research findings of the association between circadian rhythm gene polymorphisms and MetS and its comorbidities are not consistent. In this study, a review of the association of circadian clock gene polymorphisms with overall MetS risk was performed. In addition, a meta-analysis was performed to clarify the association between circadian clock gene polymorphisms and MetS susceptibility based on available data. The PubMed and Scopus databases were searched for studies reporting the association between circadian rhythm gene polymorphisms (ARNTL, BMAL1, CLOCK, CRY, PER, NPAS2, REV-ERBα, REV-ERBβ, and RORα) and MetS, and its comorbidities diabetes, obesity, and hypertension. Thirteen independent studies were analyzed with 17,381 subjects in total. The results revealed that the BMAL1 rs7950226 polymorphism was associated with an increased risk of MetS in the overall population. In contrast, the CLOCK rs1801260 and rs6850524 polymorphisms were not associated with MetS. This study suggests that some circadian rhythm gene polymorphisms might be associated with MetS in different populations and potentially used as predictive biomarkers for MetS.

Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Hannah M. Costello ◽  
Michelle L. Gumz
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Clock Genes ◽  
Adverse Outcomes ◽  
The Body ◽  
Perivascular Adipose Tissue ◽  
Area Of Interest ◽  
Recent Advances ◽  
Increased Risk ◽  
Peripheral Clocks

Accumulating evidence suggests that the molecular circadian clock is crucial in blood pressure (BP) control. Circadian rhythms are controlled by the central clock, which resides in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks throughout the body. Both light and food cues entrain these clocks but whether these cues are important for the circadian rhythm of BP is a growing area of interest. The peripheral clocks in the smooth muscle, perivascular adipose tissue, liver, adrenal gland, and kidney have been recently implicated in the regulation of BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. In this review, we summarize the most recent advances in peripheral clocks as BP regulators, highlight the adverse outcomes of disrupted circadian BP rhythm in hypertension, and provide insight into potential future work in areas exploring the circadian clock in BP control and chronotherapy. A better understanding of peripheral clock function in regulating the circadian rhythm of BP will help pave the way for targeted therapeutics in the treatment of circadian BP dysregulation and hypertension.

scholarly journals A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude

2020 ◽  
Vol 295 (11) ◽  
pp. 3518-3531 ◽  
Author(s):  
Yagmur Umay Doruk ◽  
Darya Yarparvar ◽  
Yasemin Kubra Akyel ◽  
Seref Gul ◽  
Ali Cihan Taskin ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Circadian Clock ◽  
Small Molecules ◽  
Metabolic Diseases ◽  
Nuclear Translocation ◽  
Accelerated Aging ◽  
Proper Function ◽  
Potential Candidate

Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ∼2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.

Zebrafish arylalkylamine-N-acetyltransferase genes – targets for regulation of the circadian clock

2006 ◽  
Vol 36 (2) ◽  
pp. 337-347 ◽  
Author(s):  
L Appelbaum ◽  
D Vallone ◽  
A Anzulovich ◽  
L Ziv ◽  
M Tom ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Pineal Gland ◽  
Circadian Clock ◽  
Fluorescent Protein ◽  
Transgenic Fish ◽  
Constant Darkness ◽  
Rhythmic Expression ◽  
E Box

Daily rhythms of melatonin production are controlled by changes in the activity of arylalkylamine-N-acetyltransferase (AANAT). Zebrafish possess two aanats, aanat1 and aanat2; the former is expressed only in the retina and the latter is expressed in both the retina and the pineal gland. Here, their differential expression and regulation were studied using transcript quantification and transient and stable in vivo and in vitro transfection assays. In the pineal gland, the aanat2 promoter exhibited circadian clock-controlled activity, as indicated by circadian rhythms of Enhanced green fluorescent protein (EGFP) mRNA in AANAT2:EGFP transgenic fish. In vivo transient expression analyses of the aanat2 promoter indicated that E-box and photoreceptor conserved elements (PCE) are required for expression in the pineal gland. In the retina, the expression of both genes was characterized by a robust circadian rhythm of their transcript levels. In constant darkness, the rhythmic expression of retinal aanat2 persisted while the aanat1 rhythm disappeared; indicating that the former is controlled by a circadian clock and the latter is also light driven. In the light-entrainable clock-containing PAC-2 zebrafish cell line, both stably transfected aanat1 and aanat2 promoters exhibited a clock-controlled circadian rhythm, characteristic for an E-box-driven expression. Transient co-transfection experiments in NIH-3T3 cells revealed that the two, E-box- and PCE-containing, promoters are driven by the synergistic action of BMAL/CLOCK and orthehodenticle homeobox 5. This study has revealed a shared mechanism for the regulation of two related genes, yet describes their differential phases and photic responses which may be driven by other gene-specific regulatory mechanisms and tissue-specific transcription factor profiles.

scholarly journals Anti-inflammatory effect of foods and crude drugs in relation to bitter and spicy tastes

2019 ◽  
Vol 2 (4) ◽  
pp. 77 ◽  
Author(s):  
Yukinobu Ikeya ◽  
Denise A. Epp ◽  
Mikio Nishizawa
Keyword(s):  
Blood Stasis ◽  
Earth Metal ◽  
The Body ◽  
Kampo Medicine ◽  
Crude Drug ◽  
Wood Fire ◽  
Five Elements ◽  
Crude Drugs ◽  
Anti Inflammatory ◽  
Pharmacological Function

Backround: In Kampo medicine as well as traditional Chinese medicine, each crude drug is classified by four properties (cold, cool, warm, and heat), five tastes (sour, bitter, sweet, spice, and salt) based on the Yin-yang and five elements (wood, fire, earth, metal, water) theory. The four properties and five tastes are greatly related to the medicinal efficacy of the crude drug in Kampo medicine. The pharmacological function of crude drugs is called "Yakuno" in Japanese. Examples of Yakuno include various functions such as clearing heat and removing blood stasis. Crude drugs with properties classified as cold or cool have the function to clear heat as they cool the body. Crude drugs classified as bBitter also have the function to clear heat. We speculated that anti-inflammatory constituents are included in crude drugs and food that are classified as cold or cool in property and bitter in taste.Keywords: crude drug, Kampo medicine, food, property, taste, nitric oxide, inflammation, pharmacological function

scholarly journals Glucocorticoids Reset the Nasal Circadian Clock in Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4302-4311 ◽  
Author(s):  
Aya Honma ◽  
Yoshiko Yamada ◽  
Yuji Nakamaru ◽  
Satoshi Fukuda ◽  
Ken-ichi Honma ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Circadian Rhythm ◽  
Circadian Clock ◽  
Nasal Mucosa ◽  
Ex Vivo ◽  
Luciferase Reporter ◽  
Peripheral Tissues ◽  
Circadian Physiology ◽  
First Time

The symptoms of allergic rhinitis show marked day-night changes that are likely to be under the control of the circadian clock, but the mechanism of this control is poorly understood. Because most peripheral tissues have endogenous circadian clocks, we examined the circadian rhythm of the clock gene product PERIOD2 (PER2) in the nasal mucosa of male mice using a luciferase reporter and demonstrated for the first time the phase-dependent effects of dexamethasone (DEX) on nasal PER2 rhythm in vivo and ex vivo. The phase shifts in PER2 rhythm caused by DEX were observed around the peak phase of serum glucocorticoids, suggesting that the circadian rhythm of endogenous glucocorticoids regulates the peripheral clock of the mouse nasal mucosa. From the viewpoint of circadian physiology, the best time to administer intranasal steroid treatment for allergic rhinitis would be when no phase shift is caused by DEX: in the early evening in diurnal humans.

scholarly journals Direct and indirect inhibition of the circadian clock protein Per1: effects on ENaC and blood pressure

2019 ◽  
Vol 316 (5) ◽  
pp. F807-F813 ◽  
Author(s):  
Abdel Alli ◽  
Ling Yu ◽  
Meaghan Holzworth ◽  
Jacob Richards ◽  
Kit-Yan Cheng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Target Genes ◽  
Single Channel ◽  
Nuclear Entry ◽  
Altered Expression ◽  
Circadian Control ◽  
Underlying Mechanisms ◽  
Clock Protein

Circadian rhythms govern physiological functions and are important for overall health. The molecular circadian clock comprises several transcription factors that mediate circadian control of physiological function, in part, by regulating gene expression in a tissue-specific manner. These connections are well established, but the underlying mechanisms are incompletely understood. The overall goal of this study was to examine the connection among the circadian clock protein Period 1 (Per1), epithelial Na+ channel (ENaC), and blood pressure (BP) using a multipronged approach. Using global Per1 knockout mice on a 129/sv background in combination with a high-salt diet plus mineralocorticoid treatment, we demonstrated that loss of Per1 in this setting is associated with protection from hypertension. Next, we used the ENaC inhibitor benzamil to demonstrate a role for ENaC in BP regulation and urinary Na+ excretion in 129/sv mice. We targeted Per1 indirectly using pharmacological inhibition of Per1 nuclear entry in vivo to demonstrate altered expression of known Per1 target genes as well as a BP-lowering effect in 129/sv mice. Finally, we directly inhibited Per1 via genetic knockdown in amphibian distal nephron cells to demonstrate, for the first time, that reduced Per1 expression is associated with decreased ENaC activity at the single channel level.

Microparticle-associated vascular adhesion molecule-1 and tissue factor follow a circadian rhythm in healthy human subjects

2008 ◽  
Vol 99 (11) ◽  
pp. 909-915 ◽  
Author(s):  
Rebecca Vince ◽  
Marie Sandström ◽  
Lee Taylor ◽  
Lars McNaughton ◽  
Gerard Laden ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Tissue Factor ◽  
Adhesion Molecule ◽  
Human Subjects ◽  
Coagulation Cascade ◽  
Healthy Human ◽  
Risk Of Death ◽  
Increased Risk ◽  
Healthy Human Subjects

SummaryAn increased risk of death or severe injury due to late-morning thrombotic events is well established. Tissue factor (TF) is the initiator of the coagulation cascade, and endothelial stresses, coupled with production of pro-coagulant microparticles (MP) are also important factors in loss of haemostasis. TF and vascular cell adhesion molecule-1 (VCAM-1) -positive cell microparticles were assessed periodically over a 24-hour (h) period in healthy human subjects to ascertain if they followed a circadian rhythm. Eleven healthy male subjects were assessed in a temperature-controlled environment with dietary intake consistent between subjects. Blood samples were taken every 4 h by venipuncture, and TF and VCAM-1 positive microparticles were quantified by flow cytometry. A significant circadian rhythm was observed in VCAM-1 MP (p=<0.0001), and a trend was shown, although not statistically significant (p=0.065) in TF microparticles. A peak was observed at 9 a.m. for VCAM-1 positive MP, followed by a decrease and subsequent peak at 9 p.m. and a minimum at 5 a.m. TF-positive MP followed a strikingly similar trend in both variation and absolute numbers with a delay. A circadian rhythm was observed in VCAM-1 and less so TF-positive MP. This has significant implications in terms of the well known increased risk of cardiovascular thrombotic events matching this data. To our knowledge this is the first such report of quantified measurements of these MP over a 24-h period and the only measurement of a 24-h variation of in-vivo blood-borne TF.

Mechanisms underlying heart failure in type 2 diabetes mellitus

2019 ◽  
pp. 37-39
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Experimental Studies ◽  
Vascular Complications ◽  
Molecular Alterations ◽  
Increased Risk ◽  
Cardioprotective Effects ◽  
Underlying Mechanisms ◽  
Cardio Vascular

The prevalence of heart failure is markedly increased in individuals with diabetes mellitus. Numerous observational studies suggest that this increased risk for heart failure can be attributed to exacerbated vascular complications and the presence of increased risk factors in diabetic subjects. In addition, experimental studies revealed the presence of a number of distinct molecular alterations in the myocardium that occur independently of vascular disease and hypertension. Many of these molecular alterations are similarly observed in failing hearts of nondiabetic patients and have thus been proposed to contribute to the increased risk for heart failure in diabetes. The interest in understanding the underlying mechanisms of impaired cardio- vascular outcomes in diabetic individuals has much increased since the demonstration of cardioprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists in recent clinical trials. The current review therefore summarizes the distinct mechanisms that have been proposed to increase the risk for heart failure in diabetes mellitus.

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