Biology subjects

Winardi, K.

Publications and source records attributed to Winardi, K..

3 recordsLinked to original sources

bioRxiv2025

Frailty, polypharmacy, deprescribing and 23-hour activity: insights from a mouse model

Management of older people with frailty commonly includes polypharmacy and deprescribing. The impacts of frailty on the outcomes of medication use and deprescribing are poorly understood; as are the effects of medication use and deprescribing on frailty and function. Here, using aged C57BL/6J (B6) male mice, we explore the effects of different chronic drug regimens (polypharmacy and monotherapy) and deprescribing on daily activities using an automated behavioral recognition cage, and explore the relationship with frailty and trajectories. At 12 months, male C57BL/6 mice were chronically administered control diet, one of 5 monotherapy diets or one of 3 polypharmacy diets with an increasing Drug Burden Index (measure of total exposure to sedative and anticholinergic medications). At 21 months of age, mice were stratified to continue treatment or to have treatment gradually withdrawn (deprescribed). At 24 months, mice were assessed using the LABORAS automated animal behavioral recognition system for 23 hours. We found that polypharmacy with increasing DBI substantially altered activity and could not be extrapolated from monotherapy response. After deprescribing, while some of the drug effects were reversible, others were irreversible, and we observed some novel changes. Exploring the relationship between frailty and LABORAS behavioral outcomes revealed unique correlations for each intervention group. Four key clusters were identified with different frailty trajectories and attributes, deficits and LABORAS outcomes. This preclinical study demonstrates that medication use and deprescribing can impact activity, frailty and frailty trajectories. The context of polypharmacy and deprescribing are important considerations to enhance translation of pre-clinical studies of frailty.

pharmacology and toxicology↗

bioRxiv2025

Effect of prescribing and deprescribing oxycodone on pain and function in a mouse model of osteoarthritis: impact of polypharmacy and sex on response

Osteoarthritis and polypharmacy are common in older adults. While not consistent with guidelines, opioid analgesia is commonly prescribed to older adults with osteoarthritis and other causes of chronic non-cancer pain. Long term use of opioids is associated with tolerance, addiction, loss of efficacy and adverse events. Thus, deprescribing (reducing or ceasing) opioids is often required. The effect of polypharmacy on the efficacy and safety of opioid prescribing and deprescribing in this setting is poorly understood. Here we aimed to assess the effects of chronic oxycodone, as monotherapy and in polypharmacy (oxycodone, citalopram, simvastatin, oxybutynin, and metoprolol), and of deprescribing oxycodone, on allodynia, physical and cognitive function, and daily activities in middle-aged, osteoarthritic male and female C57BL/6J mice (n=11-15/ group). Only oxycodone monotherapy reduced mechanical allodynia after 6 weeks of treatment. Chronic polypharmacy with oxycodone transiently increased mechanical allodynia in the injured limb and caused marked reductions in mobility, maximum walking speed, activities of daily living, and increased anxiety. Polypharmacy also altered daily activities detected by an automated animal behaviour recognition cage. Sex differences in treatment response were observed in frailty measurements and activity over 23 hours. Deprescribing oxycodone was well tolerated and did not alter physical or cognitive function but did reverse some of the daily activity changes and mechanical allodynia in polypharmacy treated animals only. This clinically relevant preclinical model provides an opportunity to understand the effects of prescribing and deprescribing opioids in older adults with osteoarthritis, including the impact of comedications and sex.

pharmacology and toxicology↗

bioRxiv2024

Nuclear actin and DNA replication stress regulate the recruitment of human telomerase to telomeres

The recruitment of telomerase to telomeres is a tightly regulated process which is stimulated by replication stress and mediated by the DNA damage response regulatory kinase ATR. Here, we demonstrate that nuclear filamentous actin is important for telomerase recruitment under endogenous and replication stress conditions in immortal human cells. Inhibition of nuclear actin polymerization decreases the presence of telomerase at telomeres. This process is regulated by both ATR and mTOR kinases, and employs other regulators of actin structure and function, such as WASP, ARP2/3 and myosin. Nuclear filamentous actin serves as a site for telomerase recruitment, which is mediated by telomere tethering on actin fibres in response to replication stress, allowing telomerase to localize to telomeres containing stalled replication forks. Overall, these data demonstrate that, in human cells which express telomerase, telomeric replication stress triggers the recruitment of telomerase to telomeres via a nuclear actin network, enabling telomere length maintenance.

cancer biology↗