Biology subjects

Marsolais, D.

Publications and source records attributed to Marsolais, D..

3 recordsLinked to original sources

bioRxiv2026

Circadian disruption alters hepatic calcium hemostasis, endocannabinoidome and mitochondria through N -docosahexaenoyl ethanolamide-GPR110 signaling

Circadian rhythm disruption is associated with metabolic and inflammatory disorders; however, the mechanisms linking circadian dysfunction to endocannabinoidome (eCBome) signaling and mitochondrial metabolism remain unclear. In our previous in vivo study, constant light exposure altered hepatic eCBome profiles, reduced N-acylethanolamines (NAEs), increased monoacylglycerols (MAGs), and elevated inflammatory cytokines. Here, we investigated the underlying mechanisms using CRISPR/Cas9-generated BMAL1 knockout (KO) HepG2 cells as an in vitro model of circadian alteration. The BMAL1 KO model showed broad lipid remodeling characterized by increased fatty acids, prostaglandins, and MAGs together with reduced NAEs and enhanced lipid accumulation. These changes were accompanied by increased inflammatory signaling and cytokine production. Among the assessed genes, GPR110 was significantly altered in mice exposed to constant light (in vivo study) and BMAL1 KO model and emerged as a potential mediator linking circadian signaling to mitochondrial function. BMAL1 KO cells also exhibited significantly increased calcium (Ca{superscript 2}+) levels in mitochondria and the endoplasmic reticulum (ER), along with attenuation of mitochondrial and glycolytic ATP production. BMAL1KO did not abolish the rhythmicity of NAEs level over 24 hours from medium deprivation and read ministration except for N-docosahexaenoyl-ethanolamide (DHEA). Further, experiments showed that DHEA acts through GPR110 and suppress inflammatory lipid-associated pathways, enhances ATP production, and increases mitochondrial and ER Ca{superscript 2}+ accumulation and inflammatory signaling. Together, these mitochondrial Ca{superscript 2}+ signaling, and inflammation in hepatocytes, highlighting DHEA-GPR110 signaling as a potential regulator of hepatic metabolic homeostasis. HighlightsCircadian disruption increases hepatic monoacylglycerols and decreases N-acylethanolamines. Circadian disruption decreases ATP production and enhances mitochondrial and endoplasmic reticulum Ca{superscript 2}+ levels in hepatocytes DHEA-GPR110 signaling regulates hepatocytes mitochondrial Ca{superscript 2}+ dynamics and ATP production GPR110-mediated Ca{superscript 2}+ signaling significantly alters hepatocytes glycolysis and glycolytic ATP production

Cell Biology↗

bioRxiv2026

Testosterone alleviates inflammation but increases the methacholine response in mice with allergic lung inflammation

Testosterone seems protective against asthma, but the underlying mechanisms are uncertain. Herein, the effect of testosterone was investigated on several features of experimental asthma. Systemic testosterone was first altered to subphysiological, physiological, or supraphysiological levels in male BALB/c mice through orchiectomy and testosterone supplementation. Testosterone (0.25 mg/day/30 g of body weight) was delivered continuously during 20 days using an implanted pump. At day 10, each group was exposed intranasally to either saline or house dust mite (HDM) once daily for 10 consecutive days to induce allergic lung inflammation. The day after the last exposure, respiratory mechanics was measured at baseline and in response to nebulized methacholine. Bronchoalveolar lavages (BAL) and lung tissues were also collected to quantify inflammation. Baseline respiratory mechanics were altered in mice with subphysiological levels of testosterone, with signs of small airway narrowing heterogeneity and closure. Testosterone drastically inhibited the HDM-induced inflammation. Yet, testosterone also increased the response to methacholine, as well as hysteresis, which are both indicators of enhanced airway smooth muscle activity. While it suggests that testosterone increases the contractility of the smooth muscle, it simultaneously and markedly inhibits inflammation. Explanations as to how these outcomes may lead to protection in asthma are discussed.

physiology↗

bioRxiv2024

Airway smooth muscle tone curbs hyperresponsiveness in experimental asthma

Background & ObjectivesA sustained contraction of airway smooth muscle, hereinafter called tone, increases the response to methacholine in healthy mice and humans. However, the effect of tone in the context of an active inflammation remains to be investigated. The objective of the present study was to test the effect of tone on the in vivo response to methacholine in mice during an active inflammatory phase of experimental asthma. MethodsMale BALB/c mice were exposed once-daily to either intranasal saline or house dust mite for 10 consecutive days to induce experimental asthma. They then underwent one of two methacholine challenges 24 h after the last exposure. While the same cumulative dose was administered in both challenges, one was preceded by a 20-min period of tone induced by nebulizing low doses of methacholine at 5-min intervals. Respiratory mechanics were monitored before and throughout the methacholine challenge by oscillometry. Bronchoalveolar lavages (BAL) and histology were also performed. ResultsBAL inflammation and histological alterations were consistent with experimental asthma. In accordance with previous studies, tone potentiated the response to methacholine in control mice, mainly by stiffening the lung periphery. The lung was even stiffer upon methacholine challenge during an active phase of inflammation in mice with experimental asthma, but this was not further potentiated by tone. In fact, in mice with experimental asthma, tone mitigated hyperresponsiveness by preventing further airway narrowing and, more importantly, small airway narrowing heterogeneity and closure. ConclusionDuring an active inflammatory phase of experimental asthma, tone protects against hyperresponsiveness. Take-home messageThe effect of airway smooth muscle tone on the methacholine response was investigated in mice with or without experimental asthma. While tone potentiated the methacholine response in control mice, it mitigated hyperresponsiveness in experimental asthma. These results unveiled a protective role of the airway smooth muscle in experimental asthma.

physiology↗