Biology subjects

Dahlka, J.

Publications and source records attributed to Dahlka, J..

3 recordsLinked to original sources

bioRxiv2025

Bidirectional Crosstalk Between Sleep and Pulmonary Arterial Hypertension

BackgroundPulmonary Arterial Hypertension (PAH) is a devastating cardiopulmonary disease characterized by pulmonary vascular remodeling due to vascular cells dysfunction. Among other clinical signs, emerging data suggest poor sleep quality in patients with PAH; however, how poor sleep impacts hemodynamic burden, symptom severity, and pulmonary vascular remodeling during PAH progression remains unknown. MethodsWe used two models of sleep disturbances (sleep fragmentation and chronic jet lag) and different mouse models of PAH to determine the effects of poor sleep on PAH. We carried out timepoint quantitative RT-PCR analyses to define the clock gene oscillations in human pulmonary artery smooth muscle cells (PASMCs) isolated from non-PAH and PAH patients. Bulk RNA-sequencing analysis, immunostaining, and proliferation assays were used to explore the mechanisms by which poor sleep impacts PAH. Electroencephalogram and Electromyogram recordings (EEG/EMG) were used to determine whether PAH affects sleep in mice. ResultsPoor sleep exacerbated right ventricular dysfunction, pulmonary vascular remodeling, and PAH. RNA-seq and immunostaining analyses showed that poor sleep induces lung inflammation. Inflammation affected the pulmonary vascular molecular clock to drive PASMC hyperproliferation and increased migration. SMC-specific deletion of Bmal1 protected mice from RV dysfunction, pulmonary vascular remodeling, and PAH. EEG/EMG measurements demonstrated that PAH causes poor sleep quality in mice. Lastly, we showed that improving sleep via melatonin delivery and blunting inflammation with clodronate inhibited pulmonary vascular remodeling and PAH. ConclusionsOur study demonstrates that PAH causes poor sleep which in turn induces inflammation, increases PASMC proliferation, and exacerbates PAH. This suggests that the relationship between PAH and poor sleep is a self-amplifying cycle, and that a combination of hypnotic and anti-inflammatory drugs may give PAH patients better clinical outcomes. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIPAH causes poor sleep quality which in turn induces lung inflammation, PASMC proliferation, and exacerbated PAH. C_LIO_LIBmal1 rhythmicity is disrupted, and its expression is increased in lungs of patients with PAH. C_LIO_LISMC-specific deletion of Bmal1 protects from PAH. C_LIO_LIImproving sleep quality and blunting inflammation attenuates PAH. C_LI What Are the Clinical Implications?O_LIBmal1 represents a promising disease-modifying agent with potential for clinical translation in the treatment of PAH. C_LIO_LIA combination of hypnotic and anti-inflammatory drugs has therapeutic potential to treat PAH. C_LI

pathology↗

bioRxiv2025

A Simultaneous Inhibition of ID1 and ID3 Protects Against Pulmonary Fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are desperately needed. Inhibitor of DNA binding (ID) proteins are regulated by Transforming Growth Factor-{beta}. However, the regulation and the effects of ID proteins in IPF remain poorly understood. We aimed to assess the expression of ID proteins in IPF and determine the effects of ID proteins on human lung fibroblasts (HLF) in vitro and pulmonary fibrosis in vivo. MethodsThe expression of ID proteins in lungs and lung fibroblasts from mice and human patients with pulmonary fibrosis was evaluated. The effects of ID1/ID3 inhibition and overexpression on HLF were assessed. Genetic and pharmacological approaches were used in vivo to determine the role of ID1/ID3 in pulmonary fibrosis. ResultsID1/ID3 levels were elevated in HLFs isolated from pulmonary fibrosis-diseased patients and mice. ID1/ID3 knockdown decreased IPF-diseased HLF proliferation and differentiation into myofibroblasts. Bleomycin-exposed ID1/ID3 KO mice displayed improved lung function and presented with decreased lung fibrosis when compared to WT mice. A pharmacological inhibitor of ID1/ID3 decreased IPF-diseased HLF proliferation and differentiation in vitro and attenuated pulmonary fibrosis in vivo. A lung specific inhibition of ID1/ID3, using adeno-associated viruses expressing short hairpins targeting ID1 and ID3, reversed pulmonary fibrosis in mice. Mechanistically, ID1/ID3 inhibition decreased fibroblast proliferation through cell cycle genes and inhibited fibroblast differentiation through the MEK/ERK pathway. ConclusionsOur data indicate that a simultaneous inhibition of ID1 and ID3 attenuates pulmonary fibrosis. ID1/ID3 inhibition holds potential as a novel therapeutic treatment for IPF.

pathology↗

bioRxiv2024

Increased interaction between connexin43 and microtubules is critical for glioblastoma stem-like cell maintenance and tumorigenicity.

Glioblastoma (GBM) is the most common primary tumor of the central nervous system. One major challenge in GBM treatment is the resistance to chemotherapy and radiotherapy observed in subpopulations of cancer cells, including GBM stem-like cells (GSCs). These cells hold the ability to self-renew or differentiate following treatment, participating in tumor recurrence. The gap junction protein connexin43 (Cx43) has complex roles in oncogenesis and we have previously demonstrated an association between Cx43 and GBM chemotherapy resistance. Here, we report, for the first time, increased direct interaction between non-junctional Cx43 with microtubules in the cytoplasm of GSCs. We hypothesize that non-junctional Cx43/microtubule complexing is critical for GSC maintenance and survival and sought to specifically disrupt this interaction while maintaining other Cx43 functions, such as gap junction formation. Using a Cx43 mimetic peptide of the carboxyl terminal tubulin-binding domain of Cx43 (JM2), we successfully ablated Cx43 interaction with microtubules in GSCs. Importantly, administration of JM2 significantly decreased GSC survival in vitro, and limited GSC-derived tumor growth in vivo. Together, these results identify JM2 as a novel peptide drug to ablate GSCs in GBM treatment.

cancer biology↗