Biology subjects

Mach, J.

Publications and source records attributed to Mach, J..

7 recordsLinked to original sources

bioRxiv2026

Sublethal stress from polypharmacy modulates scavenging function and fenestrations in mouse liver sinusoidal endothelial cells

Polypharmacy, the concurrent use of multiple medications, is increasingly prevalent in older people and is associated with adverse outcomes such as falls, frailty, functional and cognitive decline, and increased hospitalization and mortality. The liver, as the primary site of metabolism, is exposed to varying drug concentrations during first pass metabolism, hepatic clearance and perfusion, potentially causing alterations in liver sinusoidal endothelial cells (LSEC). LSEC are specialized endothelial cells responsible for maintaining fenestrations - dynamic, transcellular pores that facilitate the exchange of substances between the blood and liver parenchyma. Disruption of fenestrations can compromise liver function, contributing to a variety of hepatic disorders. This study investigated the effects of four commonly prescribed drugs -- metoprolol, citalopram, oxybutynin and oxycodone -- on LSEC function. We examined their impact on LSEC viability, endocytosis, and fenestration morphology at both systemic steady-state and first-pass concentrations, separately and in a polypharmacy cocktail to model clinical exposure. All treatments induced sublethal metabolic changes, but effects on LSEC functions were drug- and concentration-dependent. Citalopram and oxybutynin caused dose-dependent defenestration, whereas metoprolol and oxycodone produced mild, non-dose-dependent effects. Endocytic activity was increased with oxybutynin, metoprolol, oxycodone, and the polypharmacy cocktail, while citalopram had no effect. The polypharmacy cocktail triggered synergistic defenestration at first-pass concentrations, but not at steady-state levels. These results highlight the concentration-dependent and combinatorial effects of polypharmacy on LSECs, emphasizing the need to consider endothelial responses in drug safety and pharmacokinetic assessments, particularly in patients exposed to multiple medications.

pharmacology and toxicology↗

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↗

bioRxiv2025

Water stable isotopes reveal the ecohydrological importance of stemflow for mature and juvenile European beech

O_LIStemflow of forest trees can contribute a significant fraction of water to forests water fluxes; however, it is still unclear if and to what extent trees use stemflow for water supply and how much stemflow is lost by percolating below the root zone. C_LIO_LIWe applied deuterium-enriched stemflow equivalent to a throughfall depth of 23 mm to adult Fagus sylvatica trees to trace stemflow through the soil and trees. We continuously measured in-situ water stable isotope compositions in soil and xylem water and destructively sampled xylem water in the crowns of adult labelled (n=18), unlabelled F. sylvatica (n=15) and unlabeled Picea abies (n=9), complemented by destructive xylem water sampling of neighboring juvenile F. sylvatica (n=45). C_LIO_LIStemflow water supported 3.9 - 14.0% of daily sap flux of adult labelled F. sylvatica trees. In the soil, deuterium-enriched stemflow was detectable at a max. of 0 - 0.40 m to the labelled tree. However, unlabeled juvenile trees within a distance of [~]2 m showed label water uptake, indicating rooting into soil compartments affected by stemflow label. C_LIO_LIWe demonstrate the importance of stemflow as a water source for both adult and neighboring juvenile F. sylvatica, strongly profiting from stemflow infiltration. C_LI

plant biology↗

bioRxiv2022

Displacement experiments provide evidence for path integration in Drosophila

Like many other animals, insects are capable of returning to previously visited locations using path integration. Recently, Drosophila has been added to the list of insects thought capable of this navigational memory. Existing experimental evidence, however, has a potential confound. Here we show that pheromones deposited at the site of reward might enable flies to find previously rewarding locations even without memory. Thus, we designed an experiment to determine if flies can use path integration memory despite potential pheromonal cues by displacing the flies shortly after an optogenetic reward. We found that rewarded flies returned to the location predicted by a memory-based model. Several analyses are consistent with path integration as the mechanism by which flies returned to the reward. We conclude that while pheromones may often be important in fly navigation and must be carefully controlled in future experiments, Drosophila may indeed be capable of performing path integration.

neuroscience↗

bioRxiv2022

Repurposing of mitochondria-targeted tamoxifen: Novel anti-cancer drug exhibits potent activity against major protozoan and fungal pathogens.

Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority. Author SummaryMitoTam, a mitochondrially targeted analog of tamoxifen, is a promising anti-cancer candidate drug acting by accumulating in and destabilizing cell mitochondria. In this study, we analyze its effect on a wide range of evolutionarily distinct and medically important pathogens. These include a) pathogenic fungi, Candida albicans, and Cryptococcus neoformans, ubiquitous opportunistic pathogens that cause life-threatening diseases in immunocompromised or immunologically deficient individuals; b) Plasmodium falciparum, the causative agent of human malaria; and c) several species of trypanosomatid parasites such as Trypanosoma cruzi, responsible for deadly Chagas disease in South America, Trypanosoma brucei, the causative agent of sleeping sickness in Africa, and Leishmania, the etiological agent of leishmaniasis, a spectrum of diseases ranging from usually self-healing but potentially disfiguring cutaneous and mucocutaneous leishmaniasis, to visceral leishmaniasis, which is invariably fatal if left untreated. We show that MitoTam efficiently kills these parasites in laboratory conditions and in the case of trypanosomes and leishmaniases suppress or at least slow down the infection in mouse model.

microbiology↗

bioRxiv2019

Adaptive iron utilization compensates for the lack of an inducible uptake system in Naegleria fowleri and represents a potential target for therapeutic intervention

Warm fresh water is a natural habitat for many single-celled organisms, including protozoan parasites such as the infamous brain-eating amoeba, Naegleria fowleri, which can become pathogenic for mammals, including humans. The condition caused by N. fowleri is known as primary amoebic meningoencephalitis, which is a generic and usually fatal infection of the brain with rapid onset. One of the important factors influencing a wide spectrum of pathogens, including N. fowleri, is the bioavailability of iron in the environment. The strategy of withholding iron evolved in mammalian hosts, and the different strategies of pathogens to obtain it are an important part of host-parasite interactions.\n\nIn the present study, we employ different biochemical and analytical methods to explore the effect of decreased iron availability on the cellular processes of N. fowleri. We show that under iron starvation, nonessential, iron-dependent, mostly cytosolic pathways in N. fowleri are downregulated, while the metal is utilized in the mitochondria to maintain vital respiratory processes. Surprisingly, N. fowleri fails to respond to acute shortages of iron by the induction of a reductive iron uptake system that seems to be the main iron-obtaining strategy of the parasite. Our work aims to demonstrate the importance of mitochondrial iron in the biology of N. fowleri and to explore the plausibility of exploiting it as a potential target for therapeutic interference.\n\nAuthor SummaryNaegleria fowleri is undoubtedly one of the deadliest parasites of humans, hence the name \"brain-eating amoeba\". Being dangerous, but rare, it may be regarded as a highly understudied pathogen of humans. Unfortunately, the symptoms of primary amoebic meningoencephalitis may be confused with much more common bacterial meningoencephalitis; therefore, it is quite probable that many infections caused by N. fowleri have been misdiagnosed as bacterial infections without further inquiry. In many cases, fast diagnosis is vital for commencing the correct therapy, and even then, complete success of the treatment is very rare. Our laboratory focuses on the uptake and intracellular metabolism of metals in unicellular eukaryotes, so we decided to explore the biology of N. fowleri from this aspect. Changes in the proteome, as a direct effect of iron-deficient conditions, were described, and these data were used to further explore the ways in which N. fowleri responds to these conditions on a cellular level and how its biology changes. Based on these findings, we propose that the struggle of N. fowleri to obtain iron from its host could be exploited for therapeutic interference purposes in primary amoebic meningoencephalitis patients.

biochemistry↗