scholarly journals Chrono-pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery

2022 ◽  
Vol 8 (4) ◽  
pp. 238-242
Author(s):  
Shoheb S Shaikh ◽  
Sachin M Kokate
Keyword(s):  
Circadian Clock ◽  
Biological Clock ◽  
Drug Efficacy ◽  
Therapeutic Index ◽  
Expression Of Genes ◽  
Symptom Intensity ◽  
Dosing Regimens ◽  
The Difference ◽  
Toxicity Of Drugs ◽  
And Behavior

Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The “circadian clock” is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables ‘chrono-pharmaceutical’ applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.

scholarly journals GUN4 Affects the Circadian Clock and Seedlings Adaptation to Changing Light Conditions

2021 ◽  
Vol 23 (1) ◽  
pp. 194
Author(s):  
Tao Li ◽  
Rui Wu ◽  
Zhixin Liu ◽  
Jiajing Wang ◽  
Chenxi Guo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Genes ◽  
Response Regulator ◽  
Signal Recognition Particle ◽  
Biological Clock ◽  
Chlorophyll Synthesis ◽  
Light Conditions ◽  
Strong Light ◽  
Expression Of Genes ◽  
Changing Light

The chloroplast is a key organelle for photosynthesis and perceiving environmental information. GENOME UNCOUPLED 4 (GUN4) has been shown to be required for the regulation of both chlorophyll synthesis, reactive oxygen species (ROS) homeostasis and plastid retrograde signaling. In this study, we found that growth of the gun4 mutant was significantly improved under medium strong light (200 μmol photons m−2s−1) compared to normal light (100 μmol photons m−2s−1), in marked contrast to wild-type (WT). Further analysis revealed that GUN4 interacts with SIGNAL RECOGNITION PARTICLE 54 KDA SUBUNIT (SRP43) and SRP54. RNA-seq analysis indicated that the expression of genes for light signaling and the circadian clock is altered in gun4 compared with (WT). qPCR analysis confirmed that the expression of the clock genes CLOCK-RELATED 1 (CCA1), LATE ELONGATION HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1) and PSEUDO RESPONSE REGULATOR 7 (PRR7) is significantly changed in the gun4 and srp54 mutants under normal and medium strong light conditions. These results suggest that GUN4 may coordinate the adaptation of plants to changing light conditions by regulating the biological clock, although it is not clear whether the effect is direct or indirect.

scholarly journals The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Katharina Beer ◽  
Mariela Schenk ◽  
Charlotte Helfrich-Förster ◽  
Andrea Holzschuh
Keyword(s):  
Circadian Clock ◽  
Circadian System ◽  
Evolutionary Adaptation ◽  
Solitary Bee ◽  
Daily Rhythms ◽  
Osmia Bicornis ◽  
Cavity Nesting ◽  
Impact On Survival ◽  
Life On Earth ◽  
And Behavior

AbstractLife on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee’s daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.

scholarly journals Susceptibility of Pseudomonas aeruginosa Dispersed Cells to Antimicrobial Agents Is Dependent on the Dispersion Cue and Class of the Antimicrobial Agent Used

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Jacob R. Chambers ◽  
Kathryn E. Cherny ◽  
Karin Sauer
Keyword(s):  
Antimicrobial Agents ◽  
Expression Patterns ◽  
Drug Susceptibility ◽  
Exponential Phase ◽  
Planktonic Cells ◽  
Additional Time ◽  
Modification System ◽  
Expression Of Genes ◽  
The Difference ◽  
Dispersed Cells

ABSTRACT The biofilm life cycle is characterized by the transition of planktonic cells exhibiting high susceptibly to antimicrobial agents to a biofilm mode of growth characterized by high tolerance to antimicrobials, followed by dispersion of cells from the biofilm back into the environment. Dispersed cells, however, are not identical to planktonic cells but have been characterized as having a unique transitionary phenotype relative to biofilm and planktonic cells, with dispersed cells attaching in a manner similar to exponential-phase cells, but demonstrating gene expression patterns that are distinct from both exponential and stationary-phase planktonic cells. This raised the question whether dispersed cells are as susceptible as planktonic cells and whether the dispersion inducer or the antibiotic class affects the drug susceptibility of dispersed cells. Dispersed cells obtained in response to dispersion cues glutamate and nitric oxide (NO) were thus exposed to tobramycin and colistin. Although NO-induced dispersed cells were as susceptible to colistin and tobramycin as exponential-phase planktonic cells, glutamate-induced dispersed cells were susceptible to tobramycin but resistant to colistin. The difference in colistin susceptibility was independent of cellular c-di-GMP levels, with modulation of c-di-GMP failing to induce dispersion. Instead, drug susceptibility was inversely correlated with LPS modification system and the biofilm-specific transcriptional regulator BrlR. The susceptibility phenotype of glutamate-induced dispersed cells to colistin was found to be reversible, with dispersed cells being rendered as susceptible to colistin within 2 h postdispersion, though additional time was required for dispersed cells to display expression of genes indicative of exponential growth.

scholarly journals Influence of Hyperthermia on Efficacy and Uptake of Carbon Nanohorn-Cisplatin Conjugates

2014 ◽  
Vol 136 (2) ◽  
Author(s):  
Matthew R. DeWitt ◽  
Allison M. Pekkanen ◽  
John Robertson ◽  
Christopher G. Rylander ◽  
Marissa Nichole Rylander
Keyword(s):  
Cellular Uptake ◽  
Near Infrared ◽  
Drug Efficacy ◽  
Infrared Light ◽  
Exterior Surface ◽  
Mild Hyperthermia ◽  
Carbon Nanohorns ◽  
Thermal Enhancement ◽  
The Difference

Single-walled carbon nanohorns (SWNHs) have significant potential for use in photothermal therapies due to their capability to absorb near infrared light and deposit heat. Additionally, their extensive relative surface area and volume makes them ideal drug delivery vehicles. Novel multimodal treatments are envisioned in which laser excitation can be utilized in combination with chemotherapeutic-SWNH conjugates to thermally enhance the therapeutic efficacy of the transported drug. Although mild hyperthermia (41–43 °C) has been shown to increase cellular uptake of drugs such as cisplatin (CDDP) leading to thermal enhancement, studies on the effects of hyperthermia on cisplatin loaded nanoparticles are currently limited. After using a carbodiimide chemical reaction to attach CDDP to the exterior surface of SWNHs and nitric acid to incorporate CDDP in the interior volume, we determined the effects of mild hyperthermia on the efficacy of the CDDP-SWNH conjugates. Rat bladder transitional carcinoma cells were exposed to free CDDP or one of two CDDP-SWNH conjugates in vitro at 37 °C and 42 °C with the half maximal inhibitory concentration (IC50) for each treatment. The in vitro results demonstrate that unlike free CDDP, CDDP-SWNH conjugates do not exhibit thermal enhancement at 42 °C. An increase in viability of 16% and 7% was measured when cells were exposed at 42 deg compared to 37 deg for the surface attached and volume loaded CDDP-SWNH conjugates, respectively. Flow cytometry and confocal microscopy showed a decreased uptake of CDDP-SWNH conjugates at 42 °C compared to 37 °C, revealing the importance of nanoparticle uptake on the CDDP-SWNH conjugate's efficacy, particularly when hyperthermia is used as an adjuvant, and demonstrates the effect of particle size on uptake during mild hyperthermia. The uptake and drug release studies elucidated the difference in viability seen in the drug efficacy studies at different temperatures. We speculate that the disparity in thermal enhancement efficacy observed for free drug compared to the drug SWNH conjugates is due to their intrinsic size differences and, therefore, their mode of cellular uptake: diffusion or endocytosis. These experiments indicate the importance of tuning properties of nanoparticle-drug conjugates to maximize cellular uptake to ensure thermal enhancement in nanoparticle mediated photothermal-chemotherapy treatments.

scholarly journals Attenuated SIRT1 Activity Leads to PER2 Cytoplasmic Localization and Dampens the Amplitude of Bmal1 Promoter-Driven Circadian Oscillation

2021 ◽  
Vol 15 ◽  
Author(s):  
Atsushige Ashimori ◽  
Yasukazu Nakahata ◽  
Toshiya Sato ◽  
Yuichiro Fukamizu ◽  
Takaaki Matsui ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Circadian Clock ◽  
Posttranslational Modifications ◽  
Cultured Cells ◽  
Circadian Oscillation ◽  
Clock Proteins ◽  
Circadian Clock Proteins ◽  
Circadian Physiology ◽  
And Behavior ◽  
Robust Systems

The circadian clock possesses robust systems to maintain the rhythm approximately 24 h, from cellular to organismal levels, whereas aging is known to be one of the risk factors linked to the alternation of circadian physiology and behavior. The amount of many metabolites in the cells/body is altered with the aging process, and the most prominent metabolite among them is the oxidized form of nicotinamide adenine dinucleotide (NAD+), which is associated with posttranslational modifications of acetylation and poly-ADP-ribosylation status of circadian clock proteins and decreases with aging. However, how low NAD+ condition in cells, which mimics aged or pathophysiological conditions, affects the circadian clock is largely unknown. Here, we show that low NAD+ in cultured cells promotes PER2 to be retained in the cytoplasm through the NAD+/SIRT1 axis, which leads to the attenuated amplitude of Bmal1 promoter-driven luciferase oscillation. We found that, among the core clock proteins, PER2 is mainly affected in its subcellular localization by NAD+ amount, and a higher cytoplasmic PER2 localization was observed under low NAD+ condition. We further found that NAD+-dependent deacetylase SIRT1 is the regulator of PER2 subcellular localization. Thus, we anticipate that the altered PER2 subcellular localization by low NAD+ is one of the complex changes that occurs in the aged circadian clock.

scholarly journals Perbedaan Perkembangan Motorik Bayi Pasca Pemberian Stimulasi Pijatan dan Berenang

2016 ◽  
Vol 2 (1) ◽  
pp. 42-44
Author(s):  
Aryunani Aryunani ◽  
Pipit Festi Wilianarti
Keyword(s):  
Treatment Group ◽  
Motor Development ◽  
Wilcoxon Test ◽  
Growth Disorders ◽  
Data Sampling ◽  
Developmental Growth ◽  
Before And After ◽  
The Difference ◽  
And Behavior ◽  
Attitudes And Behavior

Developmental growth disorders in children under five will result in a decrease in the formation of attitudes and behavior of children in the future. These disorders can be prevented by stimulating development. This study used a quasy experimental design. This research was carried out for 4 months in Privately Practising Midwives in Sidotopo village of Semampir sub-district of North Surabaya with a sample of infants aged 6 to 12 months. Data sampling used consecutive sampling collected through observation using the observation sheet. Data were analyzed using Wilcoxon test to see the difference in gross motor before and after treatment in  the treatment group. In  the treatment group 40% infant experienced an increase of 1-2 segment of motor development and 60% had an increase of 3-4 segments.  

scholarly journals Behavior and Energy Losses of Cows during the Period of Low Temperatures

2021 ◽  
Vol 24 (5) ◽  
pp. 46-53
Author(s):  
Oleksandr O. Borshch ◽  
Oleksandr V. Borshch ◽  
Yurii Mashkin ◽  
Vasyl Malina ◽  
Maxim Fedorchenko
Keyword(s):  
Low Temperatures ◽  
Heat Insulation ◽  
Energy Losses ◽  
Strong Wind ◽  
The Past ◽  
Air Temperatures ◽  
The Difference ◽  
And Behavior ◽  
Positive Effect ◽  
Moderate Climate

Over the past 20 years, dairy farms in Ukraine have been actively introducing the keeping of cows in easy-to-assemble premises. However, in a moderate climate (with four distinct year seasons), the issues of microclimate, energy losses of animals and their behavior during the cold period of the year for keeping in such premises have not been fully studied. The purpose of this work was to study the influence of the heat insulation elements use of side curtains in easy-to-assemble premises during the period of low temperatures on microclimate, energy outgoings for thermoregulation and behavior of cows. The research conducted in the central part of Ukraine (Kyiv region). The research was conducted during January-February (29-43 days of the year) 2021. This period characterized by low average daily temperatures of -12.2– -18.7°С, strong wind gusts and daily precipitation in the form of snow. Two easy-toassemble premises for 400 heads were used for research. Parameters of placements (LxWxH): 150х32х10.5 m. The first one was without the use of curtains heat insulation elements, and the second one was with these elements of heat insulation. It was found that the use of polycarbonate wall heat insulation elements had a positive effect on the microclimate in the placement during the period of low temperatures. Indicators of average daily air temperatures in the placement were 3.2 and 8.8°C higher compared to the temperature in the same premise without the use of heat insulation elements and the environment. The wind speed also differed by 0.18 and 11.04 m/s, respectively. In addition, the heat insulation of the walls affected the temperature under the lying cow (+1.8°C), energy outgoings for thermoregulation (-1.93 MJ) and the number of cows that lay in the period of the lowest temperatures (+3.23-9.83%) compared to the placement without heat insulation elements. The difference in temperature of rubber carpet in the compared premises was significant: +3.3°C in the premises with heat insulation elements compared to the premises without heat insulation

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