Duong, H. P. | bioRxiv Science

bioRxiv2022

The effect of the menstrual cycle on the circulating microRNA pool in human plasma: a pilot study

Study questionDo ovarian hormones levels influence cf-miRNA expression across the menstrual cycle? Summary answerMeasures of ovarian hormones should be rigorously included in future studies assessing cf-miRNA expression in females and used as time-varying confounders. This exploratory study suggests that cf-miRNAs may play an active role in the regulation of the female cycle in various target tissues. What is known alreadyCell-free or "circulating" miRNAs (cf-miRNAs) are secreted from tissues into most physiological fluids, including plasma, where they play a role in cross-tissue communication. Endogenous and exogenous factors, including sex hormones, regulate cellular miRNA expression levels. Plasma cf-miRNA levels vary with numerous pathological and physiological conditions, including in females. Participants/materials, setting, methodsWe conducted an exploratory study where blood samples were collected from sixteen eumenorrheic females in the early follicular phase, the ovulation phase and the mid-luteal phase of the menstrual cycle. Ovarian hormones oestrogen, progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in serum by electrochemiluminescence. The expression levels of 179 plasma-enriched miRNAs were profiled using a PCR-based panel, including stringent internal and external controls to account for the potential differences in RNA extraction and reverse-transcription stemming from low-RNA input samples. Study design, size, durationThis was a prospective monocentric study conducted between March and November 2021. Main results and the role of chanceThis exploratory study suggests that cf-miRNAs may play an active role in the regulation of the female cycle in various target tissues. Linear mixed-models adjusted for the relevant variables showed numerous associations between phases of the menstrual cycle, ovarian hormones and plasma cf-miRNA levels. Validated gene targets of the cf-miRNAs varying with the menstrual cycle were enriched within the female reproductive tissues and primarily involved in cell proliferation and apoptosis. Wider implications of the findingsMeasures of ovarian hormones should be rigorously included in future studies assessing cf-miRNA expression in females and used as time-varying confounders. Limitations, reasons for cautionOur study was conducted on a relatively small cohort of patients. However, it was tightly controlled for endogenous and exogenous confounders, which is critical to ensure robust and reproducible cf-miRNA research. Wider implications of the findingsOur results reinforce the importance of accounting for female-specific biological processes in physiology research by implementing practical or statistical mitigation strategies during data collection and analysis. Study funding/competing interest(s)This study was supported by the clinique romande de readaptation, Sion, Switzerland. Prof. Severine Lamon, is supported by an Australian Research Council Future Fellowship (FT10100278). The authors declare no competing interest Trial registration numberN/A.

physiology↗

bioRxiv2018

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.\n\nAuthor summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungus Madurella mycetomatis. Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

pharmacology and toxicology↗