Molecular clocks are responsible for defining 24-h cycles of behaviour and physiology that are called circadian rhythms. Several structures and tissues are responsible for generating these circadian rhythms and are named circadian clocks. The suprachiasmatic nucleus of the hypothalamus is believed to be the master circadian clock receiving light input via the optic nerve and aligning internal rhythms with environmental cues. Studies using both in vivo and in vitro methodologies have reported the relationship between the molecular clock and sex hormones. The circadian system is directly responsible for controlling the synthesis of sex hormones and this synthesis varies according to the time of day and phase of the estrous cycle. Sex hormones also directly interact with the circadian system to regulate circadian gene expression, adjust biological processes, and even adjust their own synthesis. Several diseases have been linked with alterations in either the sex hormone background or the molecular clock. So, in this chapter we aim to summarize the current understanding of the relationship between the circadian system and sex hormones and their combined role in the onset of several related diseases.

Colorectal cancer (CRC) is third cancer causing death in the world. CRC is associated with disrupting the circadian rhythm (CR), closely associating the CRC progression and the dysregulation of genes involved in the biological clock. In this study, we aimed to understand the circadian rhythm changes in patients diagnosed with CRC. We used the GEO database with the ID GSE46549 for our analysis, which consists of 32 patients with CRC and one as normal control. Our study has identified five essential genes involved in CRC, HAPLN1, CDH12, IGFBP5, DCHS2, and DOK5, and had different enriched pathways, such as the Wnt-signaling pathway, at different time points of study. As a part of our study, we also identified various related circadian genes, such as CXCL12, C1QTNF2, MRC2, and GLUL, from the Circadian Gene Expression database, that played a role in circadian rhythm and CRC development. As circadian timing can influence the host tissue's ability to tolerate anticancer medications, the genes reported can serve as a potential drug target for treating CRC and become beneficial to translational settings.

The circadian rhythm is the timing mechanism that creates approximately 24-hour rhythms in cellular and bodily functions in almost all living species. These internal clock systems enable living organisms to predict and respond to daily changes in their environment, optimizing temporal physiology and behavior. Circadian rhythms are regulated by both genetic and environmental risk factors. Circadian rhythms play an important role in maintaining homeostasis at the systemic and tissue levels. Disruption of this rhythm lays the groundwork for human health and disease. Disruption in these rhythms increases the susceptibility to many diseases, such as cancer, psychiatric disorders, and neurodegenerative diseases. In this chapter, the characteristics of circadian rhythm and its relationship with diseases will be discussed.

Cellular senescence is an irreversible proliferation arrest in response to cellular damage and stress. Although cellular senescence is a highly stable cell cycle arrest, it can influence many physiological, pathological, and aging processes. Cellular senescence can be triggered by various intrinsic and extrinsic stimuli such as oxidative stress, mitochondrial dysfunction, genotoxic stress, oncogenic activation, irradiation and chemotherapeutic agents. Senescence is associated with several molecular and phenotypic alterations, such as senescence-associated secretory phenotype (SASP), cell cycle arrest, DNA damage response (DDR), senescence-associated β-galactosidase, morphogenesis, and chromatin remodeling. Cellular senescence is a regular physiological event involved in tissue homeostasis, embryonic development, tissue remodeling, wound healing, and inhibition of tumor progression. Mitochondria are one of the organelles that undergo significant morphological and metabolic changes associated with senescence. Recent evidence unraveled that inter-organelle communication regulates cellular senescence, where mitochondria form a highly complex and dynamic network throughout the cytoplasm with other organelles, like the endoplasmic reticulum. An imbalance in organelle interactions may result in faulty cellular homeostasis, which contributes to cellular senescence and is associated with organ aging. Since mitochondrial dysfunction is a common characteristic of cellular senescence and age-related diseases, mitochondria-targeted senolytic or redox modulator senomorphic strategies help solve the complex problems with the detrimental consequences of cellular senescence. Understanding the regulation of mitochondrial metabolism would provide knowledge on effective therapeutic interventions for aging and age-related pathologies. This chapter focuses on the biochemical and molecular mechanisms of senescence and targeting senescence as a potential strategy to alleviate age-related pathologies and support healthy aging.

Colorectal cancer (CRC) is a form of cancer characterized by many symptoms and readily metastasizes to different organs in the body. Circadian rhythm is one of the many processes that is observed to be dysregulated in CRC-affected patients. In this study, we aim to identify the dysregulated physiological processes in CRC-affected patients and correlate the expression profiles of the circadian clock genes with CRC-patients' survival rates. We performed an extensive microarray gene expression pipeline, whereby 471 differentially expressed genes (DEGs) were identified, following which, we streamlined our search to 43 circadian clock affecting DEGs. The Circadian Gene Database was accessed to retrieve the circadian rhythm-specific genes. The DEGs were then subjected to multi-level functional annotation, i.e., preliminary analysis using ClueGO/CluePedia and pathway enrichment using DAVID. The findings of our study were interesting, wherein we observed that the survival percentage of CRC-affected patients dropped significantly around the 100th-month mark. Furthermore, we identified hormonal activity, xenobiotic metabolism, and PI3K-Akt signaling pathway to be frequently dysregulated cellular functions. Additionally, we detected that the ZFYVE family of genes and the two genes, namely MYC and CDK4 were the significant DEGs that are linked to the pathogenesis and progression of CRC. This study sheds light on the importance of bioinformatics to simplify our understanding of the interactions of different genes that control different phenotypes.

Circadian rhythms are autonomous oscillators developed by the molecular circadian clock, essential for coordinating internal time with the external environment in a 24-h daily cycle. In mammals, this circadian clock system plays a major role in all physiological processes and severely affects human health. The regulation of the circadian clock extends beyond the clock genes to involve several clock-controlled genes. Hence, the aberrant expression of these clock genes leads to the downregulation of important targets that control the cell cycle and the ability to undergo apoptosis. This may lead to genomic instability and promotes carcinogenesis. Alteration in the clock genes and their modulation is recognized as a new approach for the development of effective treatment against several diseases, including cancer. Until now, there has been a lack of understanding of circadian rhythms and cancer disease. For that, this chapter aims to represent the core components of circadian rhythms and their function in cancer pathogenesis and progression. In addition, the clinical impacts, current clock drugs, and potential therapeutic targets have been discussed.

Neurodegenerative diseases are characterized by degeneration or cellular atrophy within specific structures of the brain. Neurons are the major target of neurodegeneration. Neurons utilize 75-80% of the energy produced in the brain. This energy is either formed by utilizing the glucose provided by the cerebrovascular blood flow or by the in-house energy producers, mitochondria. Mitochondrial dysfunction has been associated with neurodegenerative diseases. But recently it has been noticed that neurodegenerative diseases are often associated with cerebrovascular diseases. Cerebral blood flow requires vasodilation which to an extent regulated by mitochondria. We hypothesize that when mitochondrial functioning is disrupted, it is not able to supply energy to the neurons. This disruption also affects cerebral blood flow, further reducing the possibilities of energy supply. Loss of sufficient energy leads to neuronal dysfunction, atrophy, and degeneration. In this chapter, we will discuss the metabolic modifications of mitochondria in aging-related neurological disorders and the potential of phytocompounds targeting them.

We know that numerous proteins expressed in the heart are influenced by environmental signals (such as light and diet), which cause either an increase or decrease in their expression. Cardiovascular health is sensitive to diet composition (macronutrient content), as well as the percentage of energy, frequency and regularity of meal intake during the 24-hour cycle, and the fasting period. Furthermore, light is an important synchronizer of the circadian clock and, in turn, of several physiological processes, among them cardiovascular physiology. In this chapter, we address the effects of these environmental cues and the known mechanisms that lead to this variation in protein expression in the heart, as well as cardiac function.

Circadian rhythm is an endogenous timing system that allows an organism to anticipate and adapt to daily changes and regulate various physiological variables such as the sleep-wake cycle. This rhythm is governed by a molecular circadian clock mechanism, generated by a transcriptional and translational feedback loop (TTFL) mechanism. In mammals, TTFL is determined by the interaction of four main clock proteins: BMAL1, CLOCK, Cryptochromes (CRY), and Periods (PER). BMAL1 and CLOCK form dimers and initiate the transcription of clock-controlled genes (CCG) by binding an E-box element with the promotor genes. Among CCGs, PERs and CRYs accumulate in the cytosol and translocate into the nucleus, where they interact with the BMAL1/CLOCK dimer and inhibit its activity. Several epidemiological and genetic studies have revealed that circadian rhythm disruption causes various types of disease. In this chapter, we summarize the effect of core clock gene SNPs on circadian rhythm and diseases in humans.

The circadian clock influences almost every aspect of mammalian behavioral, physiological and metabolic processes. Being a hierarchical network, the circadian clock is driven by the central clock in the brain and is composed of several peripheral tissue-specific clocks. It orchestrates and synchronizes the daily oscillations of biological processes to the environment. Several pathological events are influenced by time and seasonal variations and as such implicate the clock in pathogenesis mechanisms. In context with viral infections, circadian rhythmicity is closely associated with host susceptibility, disease severity, and pharmacokinetics and efficacies of antivirals and vaccines. Leveraging the circadian molecular mechanism insights has increased our understanding of clock infection biology and proposes new avenues for viral diagnostics and therapeutics. In this chapter, we address the molecular interplay between the circadian clock and viral infections and discuss the importance of chronotherapy as a complementary approach to conventional medicines, emphasizing the significance of virus-clock studies.