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Influence of Biological Rhythms on Physiological Function and Diseases
- Chronopharmacology Focused on Biological Clock

Chronotherapeutic approach is based on the presence of 24 hr rhythms in physiological functions and diseases. Examples are described below. Figure 2 shows the approximate peak time of 24 hr rhythms relative to diurnally active human beings.21) The peak in serum cortisol, aldosterone, testosterone, platelet adhesiveness, blood viscosity and NK-cell activity is observed during the initial hours of daytime. Hematocrit is greatest and airway caliber (FEV1) best around the middle and afternoon hours, respectively. Insulin, cholesterol, triglycerides, platelet numbers, and uric acid peak later during the day and evening. The rhythms of basal gastric acid secretion, white blood cells (WBC), lymphocytes, prolactin, melatonin, eosinophils, adrenal corticotrophic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) shows a peak at speciˆc times during the nighttime. 24 hr rhythms in the processes that make up the pathophysiology of diseases cause prominent day-night patterns in the manifestation and severity of many medical conditions as depicted in Fig. 3.21) The onset of migraine headache is most frequent in the morning around the time of awakening from nighttime. The sneezing, runny nose, and stuŠy nose in allergic and infectious rhinitis are worst in the morning upon arising from nighttime. The symptoms of rheumatoid arthritis are worst when awaking from nighttime, while those of osteoarthritis are worst later in the day. The morbid and mortal events of myocardial infarction are greatest during the initial hours of daytime. The incidence of thrombotic and hemorrhagic stroke is greatest in the morning around the time of commencing diurnal activity. Ischemic events, chest pain, and ST-segment depression of angina are strongest during the initial three to ˆve hours of daytime. Pain and gastric distress at the onset and acute exacerbation of peptic ulcer disease are most likely in the late evening and early morning. Epilepsy seizures are common around sleep onset at night and oŠset in the morning. The symptoms of congestive heart failure are worse nocturnally. The manifestation of ST-segment elevation in Prinzmetal's angina is most frequent during the middle to latter half of the nighttime. The risk of asthma attack is greatest during nighttime. The regulatory mechanisms underlying 24 hr rhythm of physiological function and diseases should be clariˆed from the viewpoint of clock genes.

The onset of myocardial infarction occurs frequently in the early morning, and it may partly result from 24 hr rhythm of ˆbrinolytic activity. Plasminogen activator inhibitor-1 (PAI-1) activity shows a 24 hr rhythm.22) Basic helix-loop-helix (bHLH)WPAS domain transcription factors play a crucial role in controlling the biological clock. A novel bHLHWPAS protein, cycle-like factor (CLIF) is expressed in endothelial cells and neurons in the brain, including SCN. In endothelial cells, CLIF forms a heterodimer with CLOCK and up-regulates the Pai-1 gene through E-box sites. Furthermore, PER2 and CRY1 inhibit the Pai-1 promoter activation by the CLOCK:CLIF heterodimer. Namely, CLIF regulates the 24 hr rhythm of Pai-1 gene in endothelial cells. In addition, the results potentially provide a molecular basis for the morning onset of myocardial infarction. BMAL1 is a transcription factor controlling circadian rhythm and contributes to the control of adipogenesis and lipid metabolism activity in mature adipocytes.23) The level of Bmal1 mRNA increases during adipose diŠerentiation in 3T3-L1 cells. In white adipose tissues isolated from mice, BMAL1 is more highly expressed in the adipocytes fraction than the stromal-vascular fraction. Bmal1 knockout mice embryonic ˆbroblast cells fail to be diŠerentiated into adipocytes. BMAL1 induces several factors involved in lipogenesis in 3T3-L1 adipocytes. The promoter activity of these genes is stimulated by BMAL1. These factors shows a 24 hr rhythm in mice adipose tissue. Furthermore, overexpression of BMAL1 in adipocytes increases lipid synthesis activity. Thus, BMAL1 plays important roles in the regulation of adipose diŠerentiation and lipogenesis in mature adipocytes.

A sleep disorder in humans is associated with a genetic mutation aŠecting circadian clock function. Familial advanced sleep-phase syndrome (FASPS) is documented in three families.24) AŠected individuals experience early evening sleepiness and early morning awakening. Individuals with FASPS have a circadian period about an hour shorter than normal. Taking one of the FASPS families, Toh uses multiple sets of dense genomic markers to map the mutation and clariˆes that the mutant gene is hPer2.25) The hPer2 mutation changes serine 662 to a glycine (S662G). This occurs in a region of hPER2 homologous to the casein kinase I epsilon (CKIe) binding region of mPER1 and mPER2. Serine 662 is in fact part of a consensus CKIe phosphorylation site, and the S662G substitution renders the mutant protein less readily phosphorylated by CKIe than the wild-type hPER2 in vitro. Thus, a variant in human sleep behavior can be caused by a missense mutation in a clock component, hPER2, which alters the circadian period.

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