The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.

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.

Acetamiprid, a selective agonist of nicotinic acetylcholine recetors, is one of the most widely used neonicotinoids. There is limited data about toxicity of acetamiprid on male reproductive system. Therefore, the study aimed to investigate the reproductive toxic potential of acetamiprid in male rats orally treated with acetamiprid with low (12.5 mg/kg) medium (25 mg/kg) or high dose (35 mg/kg) for 90 days. According to our results, sperm concentration and plasma testosterone levels decreased in dose dependent manner. Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormeone (FSH), luteinizing hormone (LH) levels increased at low and medium dose groups and acetamiprid caused lipid peroxidation and glutathione (GSH) depletion in the testes. Histologic examinations revealed that acetamiprid induced apoptosis in medium and high dose groups and proliferation index dramatically decreased in high dose group. In conclusion, acetamiprid caused toxicity on male reproductive system in the high dose. The mechanism of the toxic effect may be associated with oxidative stress, hormonal disruptions and apoptosis. Neonicotinoids are new class of insecticides that act as selective nicotinic acetylcholine receptor (nAChR) agonist selectively in central nervous system of insects 1. Acetamiprid, one of the neonicotinoid insecticides, is commonly used for agricultural and domestic purposes against a large variety of insects 2,3. Acetamiprid has been reported to accumulate in plants and contaminate water and this can pose a potential risk for human health 4,5. Acetamiprid is absorbed easily after oral administration, and it is determined at the highest concentration in the liver, kidney, adrenal and thyroid glands 6. Some researchers showed that acetamiprid caused toxic effects on several organ systems, including the nervous, respiratory, and immune systems in the experimental models 7-9. Furthermore, it has been reported acute poisoning cases after ingestion of acetamiprid in humans 10,11. Acetamiprid has also been reported to induce reproductive toxicity in different species 12,13. The cross-sectional epidemiological study which was conducted in Kavar, (Iran) showed acetamiprid reduced the number of sperm in farmers who exposed to acetamiprid 14. As the use of acetamiprid is increasing, it is very important to identify the toxicity of acetamiprid. Additionally, acetamiprid can be used in combinations with other insecticide because of that, toxic effects and doses of acetamiprid are needed to elucidate well by chronic and subchronic toxicity studies. Acetamiprid has been shown toxic effects on many organs and systems. However, there is no satisfied information on the toxicity potential of acetamiprid on male reproductive system. In this study, it was aimed to examine the effects of acetamiprid on reproductive function of male rats in terms of oxidative stress, apoptosis, hormonal disruptions and histopathological changes. Results Effect of acetamiprid on body and testicular weights. Liver steatosis and slowness of the movem...

Radiotherapy-induced mucositis decreases the quality of life by impairing eating, swallowing, and talking and by disturbing sleep. Mucositis may also predispose to local and systemic infections and may cause interruption of radiotherapy course. We studied the efficacy of sucralfate suspension in the prevention and management of oral mucositis and pain during radiotherapy in a double-blind, placebo-controlled, randomized, prospective trial. Twenty-eight patients with head and neck cancer were included in the study. The patients were randomized to use either sucralfate mouth washing (n = 18) or placebo washing (n = 10) during irradiation. Oral mucositis and symptoms were assessed by the same physician using Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria. All patients developed varying degrees of radiation-induced mucositis. Grade 4 mucositis was not encountered in any patient. One patient had grade 1, seven patients grade 2, and two patients grade 3 mucositis in placebo group. In sucralfate group, nine patients each had grade 1 and grade 2 with no grade 3 mucositis. Patients in the sucralfate group experienced significantly lower degree of mucositis than placebo group (p < 0.05). Sucralfate mouth washing is beneficial in decreasing the intensity of radiation-induced mucositis and oral discomfort. It is cheap, easy to administer with no serious side effect, and may be routinely used in patients receiving head and neck radiotherapy.

Ozone is a strongly oxidative gas that is generally used in medical sterilization and decolorization of the effluent of textile spent dyebaths. Recent studies have reported the use of ozone to bleach textile fabrics. In this study, ozone was utilized in cotton preparation for greige, desized and scoured 100% cotton fabrics. Hydrogen peroxide bleaching was performed as the control treatment. The degree of whiteness of cotton increased after prolonged ozonation times. The scoured samples reached the whiteness level of the control (hydrogen peroxide bleached) samples. The whiteness of the hydrogen peroxide bleached, 60-min ozonated and 90-min ozonated samples all had a Stensby degree of whiteness of 81 for the scoured fabric samples. The strength loss after prolonged ozonation times was negligible. Ozonation increased the starch-size removal of the greige cotton samples and the water absorbency of the greige and desized cotton samples.

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