The paired suprachiasmatic nuclei (SCN) is the circadian pacemaker in mammals. Clock genes ultimately regulates a vast array of circadian rhythms involved in biological, physiological and behavioral process. The clock genes are closely related to sleep disorders, metabolic syndromes, and cancer diseases. Monitoring rhythm, overcoming rhythm disruption, and manipulating rhythm from the perspective of the clock genes play an important role to improve chronopharmacotherapy. Such an approach should be achieved by overcoming the new challenges in drug delivery systems that match the circadian rhythm (Chrono-DDS). Gene and antibody delivery, targeting specific molecules for certain diseases have been focused in recent studies on pharmacotherapy. One of important candidates should also be clock genes. New drugs targeting the molecular clock are being developed to manage diseases in humans. The circadian dynamics of cancer stem cells are controlled by the tumor microenvironment and provide proof for its implication in chronotherapy against triple-negative breast cancer. To examine the relationship between the circadian clock and chronic kidney disease (CKD) exacervation leads to clarify the novel molecular mechanisms causing renal malfunction in mice with CKD. A novel inhibitor of cell cycle regulatory factors has been identified and the inhibitor repressed renal inflammation in a CKD mouse model. Therefore, this review aims to introduce the role of the molecular clock in the time-dependent dosing changes in the therapeutic effect and safety of a drug and the possibility of drug discovery and development based on the molecular clock.

Sleep curtailment negatively affects cardiac activities and thus should be ameliorated by pharmacological methods. One of the therapeutic targets is melatonin receptors, which tune circadian rhythms. Ramelteon, a melatonin MT₁/MT₂ receptor agonist, has recently been developed to modulate sleep-wake rhythms. To date, the sleep-promoting effect of ramelteon has been widely delineated, but whether ramelteon treatment physiologically influences cardiac function is not well understood. To address this question, we recorded electrocardiograms, electromyograms, and electrocorticograms in the frontal cortex and the olfactory bulb of unrestrained rats treated with either ramelteon or vehicle. We detected vigilance states based on physiological measurements and analyzed cardiac and muscular activities. We found that during non-rapid eye movement (non-REM) sleep, heartrate variability was maintained by ramelteon treatment. Analysis of the electromyograms confirmed that neither microarousal during non-REM sleep nor the occupancy of phasic periods during REM sleep was altered by ramelteon. Our results indicate that ramelteon has a remedial effect on cardiac activity by keeping the heartrate variability and may reduce cardiac dysfunction during sleep.

The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14–24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14–24.

Background: Cisplatin is an effective chemotherapy but its main side effect, acute kidney injury, limits its use. Panduratin A, a bioactive compound extracted from Boesenbergia rotunda, shows several biological activities such as anti-oxidative effects. The present study investigated the nephroprotective effect of panduratin A on cisplatin-induced renal injury. Methods: We investigated the effect of panduratin A on the toxicity of cisplatin in both mice and human renal cell cultures using RPTEC/TERT1 cells. Results: The results demonstrated that panduratin A ameliorates cisplatin-induced renal toxicity in both mice and RPTEC/TERT1 cells by reducing apoptosis. Mice treated with a single intraperitoneal (i.p.) injection of cisplatin (20 mg/kg body weight (BW)) exhibited renal tubule injury and impaired kidney function as shown by histological examination and increased serum creatinine. Co-administration of panduratin A (50 mg/kg BW) orally improved kidney function and ameliorated renal tubule injury of cisplatin by inhibiting activation of extracellular signal-regulated kinase (ERK)1/2 and caspase 3. In human renal proximal tubular cells, cisplatin induced cell apoptosis by activating pro-apoptotic proteins (ERK1/2 and caspase 3), and reducing the anti-apoptotic protein (Bcl-2). These effects were significantly ameliorated by co-treatment with panduratin A. Interestingly, panduratin A did not alter intracellular accumulation of cisplatin. It did not alter the anti-cancer efficacy of cisplatin in either human colon or non-small cell lung cancer cell lines. Conclusions: The present study highlights panduratin A has a potential protective effect on cisplatin’s nephrotoxicity.

Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing nosocomial outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed, and no strategies have been established to improve adherence to PEP for healthcare workers. We aimed to retrospectively analyse adherence to PEP and the factors associated with non-adherence in healthcare workers. A survey of 221 healthcare workers who were eligible for PEP at Tokushima University Hospital in the 2016/2017 season was conducted. Once-daily oseltamivir (75 mg for 10 d) was used as the PEP regimen. Of the 221 healthcare workers, 175 received PEP and were surveyed for adherence using a questionnaire. Of the 130 healthcare workers who responded to the questionnaire, 121 (93.1%) had been vaccinated. In this survey, 82 healthcare workers (63.1%) did not fully complete PEP. Multiple logistic regression analysis revealed that physicians (odds ratio: 4.62, 95% confidence interval [CI]: 2.08–10.25) and non-vaccination (odds ratio: 9.60, 95% CI: 1.12–82.25) were the factors for non-adherence to PEP. Of the 47 healthcare workers who responded to the item regarding reasons for non-adherence, 36 (76.6%) reported forgetting to take oseltamivir or discontinuing it due to a misguided self-decision that continuation of PEP was unnecessary, and 5 (10.6%) reported discontinuing treatment due to adverse effects. In conclusion, healthcare workers, particularly physicians, had low PEP adherence owing to forgetting or stopping to take oseltamivir due to a misguided self-decision. To obtain the maximum preventive effect of PEP, medication education should be provided to endorse PEP compliance.