The circadian rhythm regulates the 24-hour physiological and behavioral cycles through endogenous molecular clocks governed by core clock genes via the transcription-translation feedback loop (TTFL). In mammals, the suprachiasmatic nucleus (SCN) serves as the central pacemaker, coordinating the timing of physiological processes throughout the body by regulating clock genes such as CLOCK, BMAL1, PER, and CRY. The molecular clocks of peripheral tissues and cells are synchronized by the SCN through TTFLs to regulate metabolism, immunity, and energy homeostasis. Numerous studies indicate that circadian rhythm disruption is closely related to obesity, type 2 diabetes, metabolic syndrome and other diseases, and the mechanism involves the dysregulation of glucose and lipid metabolism, abnormal insulin signaling and low-grade inflammation. In recent years, small-molecule compounds targeting the core clock components such as CRY, REV-ERB, and ROR have been identified and shown potential to modulate metabolic diseases by stabilizing or inhibiting the activity of key clock proteins. This review summarizes the mechanisms and advances in these compounds, and explores the challenges and future directions for their clinical translation, providing insights for chronotherapy-based metabolic disease interventions.
Humans ; Metabolic Diseases/physiopathology* ; Animals ; Circadian Rhythm/physiology* ; Biological Clocks/drug effects* ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Suprachiasmatic Nucleus/physiology*

As a rhythmic neural activity, neural oscillation exists all over the nervous system, in structures as diverse as the cerebral cortex, hippocampus, subcortical nuclei and sense organs. This review firstly presents some evidence that synchronous neural oscillations in theta and gamma bands reveal much about the origin and nature of cognitive processes such as learning and memory. And then it introduces the novel analyzing algorithms of neural oscillations, which is a directionality index of neural information flow (NIF) as a measure of synaptic plasticity. An example of application used such an analyzing algorithms of neural oscillations has been provided.
Animals ; Biological Clocks ; Brain ; physiology ; Cognition ; physiology ; Humans ; Learning ; physiology ; Memory ; physiology ; Nervous System Physiological Phenomena ; physiology ; Neural Pathways ; physiology ; Neuronal Plasticity ; physiology ; Synapses ; physiology ; Theta Rhythm ; physiology

This paper mainly introduces how to use C8051F330 MCU to design an implantable (implanted) animal activity detector with low-power technology. Through the animal activity data detected by the device, animal activity rhythm can be reflected indirectly, which provides good basis for the research of animal rhythm. Research results showed that the device, which could also provide a reliable experimental platform for further study of chronobiology (biological rhythm) in animals by detecting the signal of animal activity, has the advantages (characteristics) of good performance, lower power consumption, simple operation and highly reliability.
Animals ; Automatic Data Processing ; instrumentation ; Biological Clocks ; physiology ; Biosensing Techniques ; instrumentation ; Circadian Rhythm ; physiology ; Electrodes, Implanted ; Equipment Design ; methods ; Monitoring, Physiologic ; instrumentation ; methods ; Motor Activity ; physiology ; Signal Processing, Computer-Assisted

BACKGROUNDExtensive research toward creating a biological pacemaker by enhancement of inward depolarizing current has been performed. However, studies have mainly focused on inducing spontaneous activity and have not adequately addressed ways to improve pacemaker function. In this study we attempted to improve pacemaker function by altering connexin expression in rat mesenchymal stem cells (MSCs) to a phenotype similar to native sinus node pacemaker cells.

METHODSTo generate a biological pacemaker, MSCs were transduced with a cardiac pacemaker gene-hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), via transfection with a lentiviral vector. Funny current (I(f)) in HCN4(+) MSCs was recorded by voltage-clamp. Overexpression of connexin 45 (gene Gja7) in MSCs was achieved by transfection with the plasmid pDsRED2-N1-Gja7-RFP. Double-immunolabelling with anti-connexin 43 and anti-connexin 45 antibodies were used to identify the gap junction channels. The effects of the genetically modified MSCs on cardiomyocyte excitability were determined in MSCs cocultured with neonatal rat ventricular myocytes. Spontaneous action potentials of neonatal rat ventricular myocytes were recorded by current-clamp.

RESULTSHigh level time- and voltage-dependent inward hyperpolarization current that was sensitive to 4 mmol/L Cs(+) was detected in HCN4(+) MSCs, confirming that HCN4 acted as I(f) channels in MSCs. Connexin 43 and connexin 45 were simultaneously detected in CX45(+) MSCs. Beating frequency was (82 +/- 8) beats per minute (n = 5) in myocytes cocultured with non-transfected control MSCs, versus (129 +/- 11) beats per minute (n = 5) in myocytes cocultured with HCN4(+) MSCs. Myocytes cocultured with MSCs cotransfected with HCN4 and connexin 45 had the highest beating frequency at (147 +/- 9) beats per minute (n = 5).

CONCLUSIONThese findings demonstrate that overexpression of connexin 45 and subsequent formation of heteromeric connexin 45/connexin 43 gap junction channels in HCN4 expressing MSCs can improve their function as cardiac biological pacemakers in vitro.

Animals ; Animals, Newborn ; Biological Clocks ; physiology ; Cells, Cultured ; Connexins ; genetics ; metabolism ; Electrophysiology ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Mesenchymal Stromal Cells ; cytology ; metabolism ; physiology ; Myocytes, Cardiac ; cytology ; metabolism ; physiology ; Potassium Channels ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction

Interstitial cells of Cajal (ICCs) are located in most parts of the digestive system. Although they have been found over 100 years, their functions began to be unravelled only recently. ICCs are considered as pacemaker cells which elicit spontaneous rhythmic electric activity termed "basic electrical rhythm" or "slow waves" in gastrointestinal tract. Moreover, they also mediate neurotransmission from neurons to smooth muscle in gastrointestinal tract. ICC-like cells also exist in other visceral smooth muscles, such as urinary tract, genital system and vascular smooth muscle. In this paper we review the progress of research about the functions of visceral ICCs.
Animals ; Biological Clocks ; physiology ; Enteric Nervous System ; physiology ; Gastrointestinal Motility ; physiology ; Gastrointestinal Tract ; physiology ; Humans ; Interstitial Cells of Cajal ; physiology ; Myocytes, Smooth Muscle ; physiology ; Periodicity ; Synaptic Transmission ; physiology ; Viscera ; physiology

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.
Biological Clocks ; physiology ; Cyclic AMP ; physiology ; Cyclic Nucleotide-Gated Cation Channels ; physiology ; Electrophysiological Phenomena ; HEK293 Cells ; Humans ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Muscle Proteins ; physiology ; Patch-Clamp Techniques ; Potassium Channels ; Sinoatrial Node ; physiology ; Transfection

To explore the role of D(1)-dopamine receptor in the modulation of basic respiratory rhythm, neonatal (0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous ventilating 95% O2 and 5% CO2 and ended in 3 min. A 600-700 mum single transverse slice containing the hypoglossal nerve roots and some parts of the ventral respiratory group was cut. The preparation was quickly transferred to a recording chamber and continuously perfused with oxygen-saturated MKS at a rate of 4-6 mL/min at 27-29 degrees C. Ten medulla oblongata slice preparations were randomly divided into two groups. In group I, the preparations were perfused with perfusion solution containing D(1)-dopamine receptor specific agonist cis-(+/-)-1-(Aminomethyl)-3,4-dihydro-3-phenyl-1H-2-Benzopyran-5,6-Diolhy-drochlo-ride (A68930, 5 mumol/L) for 10 min first; after washing out, the preparations were then perfused with perfusion solution containing D(1)-dopamine receptor specific antagonist R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390, 2 mumol/L) for 10 min. In group II, after perfusion with A68930 for 10 min, the preparations were perfused with additional A68930 + SCH-23390 for 10 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrodes. The results showed that A68930 shortened the respiratory cycle (RC) and expiratory time (TE) with an increase in the integral amplitude (IA). However, SCH-23390 significantly prolonged RC and TE, and decreased IA with a decrease in inspiratory time (TI). Moreover, the effect of A68930 on the respiratory rhythm was partially reversed by additional application of A68930 + SCH-23390. These results indicate that D(1)-dopamine receptor is possibly involved in the modulation of the RRDA in the isolated neonatal rat brainstem slice.
Animals ; Animals, Newborn ; Benzazepines ; pharmacology ; Biological Clocks ; Chromans ; pharmacology ; Female ; In Vitro Techniques ; Male ; Medulla Oblongata ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine ; physiology ; Respiration

Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been investigated for generating cardiac biopacers. This article summarizes the progresses in research on recreation of cardiac biopacemakers. Genetically engineered biological pacemaker holds great promise to potentially cure severe bradycardia if critical issues, such as their stability and longevity, are properly solved.
Biological Clocks ; physiology ; Bradycardia ; therapy ; Genetic Engineering ; Heart ; Heart Rate ; Heart Ventricles ; Humans ; Ion Channels ; Myocardium ; Pacemaker, Artificial ; Sinoatrial Node

Developments of chronobiology abroad are forging ahead in elucidating the cellular and molecular basis and the influential factors of circadian clock such as light, jet lag, pharmaceutical. This article also reviews the influence of circadian system on human physiology and disease occurrence. The circadian-based therapy holds promising future and the research emphasis is on prognosis and prevention.
Biological Clocks ; Chronobiology Phenomena ; Circadian Rhythm ; physiology ; Drug Chronotherapy ; Jet Lag Syndrome

The animal time structure is a basic fact of life, no matter if one wants to study it or not. The time- dependent, mostly rhythmic, and thus to a certain degree predictable, variations of biochemical and physiological functions and of sensitivity and resistance to many environmental agents are often quite large and offer not only new insight into animal physiology and pathology but also diagnostic possibilities and therapeutic advantages. Chronobiology, chronophysiology and its subspecialities, like chronopharmacology and chronotherapy, will certainly play an important role in the clinical medicine of the future. Successful application of chronobiology to veterinary clinical medicine, however, depends critically on a thorough knowledge of its basic principles.
Animals ; Animals, Domestic/*physiology ; Behavior, Animal/*physiology ; Biological Clocks/*physiology ; Circadian Rhythm/*physiology ; Humans ; Photoperiod ; Seasons