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The control and experimental groups required for studies to be included in this systematic review. A requirement for inclusion was the incorporation of a negative control (with a vehicle control for the PTB model + a vehicle control for the intervention/treatment), treatment control (with a vehicle control for the PTB model + the active intervention/treatment), positive control (with the active PTB model + a vehicle control for the intervention/treatment), and experimental group (with the active PTB model + the active intervention/treatment)
Source publication
Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm...
Contexts in source publication
Context 1
... to the invasive nature of inducing PTB and delivering interventions, appropriate vehicle controls delivered in the same manner for both preterm model and intervention were a strict requirement. Figure 1 summarises the control groups that were required for inclusion; studies required a negative control (with a vehicle control for the PTB model and a vehicle control for the intervention/treatment), a treatment control (with a vehicle control for the PTB model and the active intervention/treatment), a positive control (with the active PTB model and a vehicle control for the intervention/treatment), and an experimental group (with the active PTB model and the active intervention/treatment). ...
Context 2
... summarised in Table 3, five out of seven interventions (from six studies) that directly targeted inflammation significantly increased gestational length in the experimental group when compared with the positive control group (p < 0.05). The positive control group received an active PTB model and a vehicle control for the treatment (Fig. ...
Citations
... Data released by WHO in 2018 showed that more than 60% of premature births occurred in countries in Africa and South Asia. In low-income countries, on average, 12% of babies are born prematurely (Miller et al., 2023). Meanwhile, in high-income countries, the average preterm birth rate is around 9%, usually the highest preterm births occur in poor families. ...
In 2020, it was recorded that the number of neonatal deaths in West Sumatra was 104, with 18 cases being the cause of prematurity, where the Mentawai Islands district had the highest ranking of neonate deaths with 44 deaths and 10 cases being the cause of prematurity. This research aims to determine the effect of administering magnesium sulfate therapy on contractions of pregnant women in cases of imminent premature labour at the Mentawai Islands District Hospital in 2021. This type of research is pre-experimental with a Grup Pretest-Post Test design because in this study a random sample was not carried out by taking samples from secondary data retrospectively. Data taken came from medical records of inpatients who had a diagnosis of premature labour (ICD Total sampling was taken with a total sample size of 48, and statistical data analysis using the McNemar test. Data from 48 research subjects experienced contractions and received magnesium sulfate therapy. During monitoring after administering magnesium sulfate, 3 subjects still experienced contractions and 45 subjects did not experience contractions. Uterine contractions occurred significantly more before magnesium sulfate therapy than after magnesium sulfate therapy (P<0.005). There is a significant relationship between administering magnesium sulfate to patients with preterm labour to stop uterine contractions at the Mentawai Islands District Hospital. Apart from being a tocolytic therapy, magnesium sulfate also has a neuroprotectant effect so it is highly recommended for therapy in cases of premature parturition.
... As source of LPS, we selected two E. coli strains (ATCC 12014 and CCUG 11412) that have been associated to human pathological scenarios of both gut [65,66] and other organs including the brain [67,68] and whose LPS toxicity was already evaluated in vitro [69,70] and in vivo [71,72]. Moreover, they have been already cultured in microfluidic devices [73,74] as representative of LPS-producing bacteria [59,72,73]. ...
The possible pathogenic impact of pro-inflammatory molecules produced by the gut microbiota is one of the hypotheses considered at the basis of the biomolecular dialogue governing the microbiota-gut-brain axis. Among these molecules, lipopolysaccharides (LPS) produced by Gram-negative gut microbiota strains may have a potential key role due to their toxic effects in both the gut and the brain.
In this work, we engineered a new dynamic fluidic system, the MINERVA device (MI-device), with the potential to advance the current knowledge of the biological mechanisms regulating the microbiota-gut molecular crosstalk. The MI-device supported the growth of bacteria that are part of the intestinal microbiota under dynamic conditions within a 3D moving mucus model, with features comparable to the physiological conditions (storage modulus of 80 ± 19 Pa, network mesh size of 41 ± 3 nm), without affecting their viability (∼ 10⁹ bacteria/mL). The integration of a fluidically optimized and user-friendly design with a bioinspired microenvironment enabled the sterile extraction and quantification of the LPS produced within the mucus by bacteria (from 423 ± 34 ng/mL to 1785 ± 91 ng/mL). Compatibility with commercially available Transwell-like inserts allows the user to precisely control the transport phenomena that occur between the two chambers by selecting the pore density of the insert membrane without changing the design of the system. The MI-device is able to provide the flow of sterile medium enriched with LPS directly produced by bacteria, opening up the possibility of studying the effects of bacteria-derived molecules on cells in depth, as well as the assessment and characterization of their effects in a physiological or pathological scenario.
In brief
Preterm birth is the leading cause of perinatal morbidity and mortality, and new therapies that delay preterm birth and improve neonatal outcomes are urgently needed. This study investigates whether ticagrelor inhibits uterine contractility and inflammation in preclinical in vitro , ex vivo (human) and in vivo (mouse) studies, to explore the potential of repurposing ticagrelor for the prevention of preterm birth.
Abstract
Preterm birth remains a significant global health challenge, affecting approximately 10% of pregnancies and resulting in one million deaths globally every year. Tocolytic agents, used to manage preterm labour, have considerable limitations including lack of efficacy, and adverse side effects, emphasising the urgent need for innovative solutions. Here, we explore repurposing an antiplatelet cardioprotective drug, ticagrelor, as a potential treatment to prevent preterm birth. Ticagrelor has demonstrated pleiotropic actions beyond platelet inhibition, including relaxant effects on smooth muscle cells and anti-inflammatory effects in models of diabetes and sepsis. As preterm birth is underscored by inflammatory processes triggering uterine contractions, these actions position ticagrelor as an attractive candidate for prevention or delay of preterm birth. Utilising primary human myometrial tissue, human myometrial cells, and a mouse model of preterm birth, we investigated ticagrelor’s potential as a safe and effective therapy for preterm birth. We showed that ticagrelor did not reduce the frequency or strength of spontaneous muscle contractions of ex vivo myometrial tissue nor did it reduce in vitro inflammation-induced contractility in myometrial cells. Additionally, ticagrelor did not exhibit the anticipated anti-inflammatory effects in myometrial cell culture experiments. In our mouse model of preterm birth, ticagrelor neither improved the preterm birth rate or fetal survival outcomes. Gene expression of pro-inflammatory cytokines and contraction-associated proteins in postpartum mouse uteri were unaltered by ticagrelor. In conclusion, ticagrelor is not a strong candidate to continue investigations in clinical trial for the treatment of preterm labour and prevention of preterm birth.
Preterm birth (PTB; delivery <37 weeks), the main cause of neonatal death worldwide, can lead to adverse neurodevelopmental outcomes, as well as lung and gut pathology. PTB is commonly associated with ascending vaginal infection. Previously, we have shown that ascending E. coli infection in pregnant mice induces PTB and reduces pup survival. Here, we demonstrate that this model recapitulates the pathology observed in human preterm neonates, namely neuroinflammation, lung injury and gut inflammation. In neonatal brains, there is widespread cell death, microglial activation, astrogliosis and reduced neuronal density. We also validate the utility of this model by assessing efficacy of maternal cervical gene therapy with an adeno-associated viral vector containing human beta defensin 3; this improves pup survival and reduces Tnfα mRNA expression in perinatal pup brains exposed to E. coli. This model provides a unique opportunity to evaluate the therapeutic benefit of preterm labour interventions on perinatal pathology.
Background:
Preterm birth is the leading cause of neonatal morbidity and mortality. Studies have shown that interleukin-1 plays a major role in the pathophysiology of preterm birth participating by inducing the production of pro-inflammatory mediators and uterine activating proteins leading to labor. More importantly, uteroplacental inflammation, associated with preterm birth parturition pathways, is detrimental to fetal tissues and leads to long term sequelae. Our group has developed an allosteric antagonist of the interleukin-1 receptor, rytvela, found to be potent and safe in preventing preterm birth by suppressing inflammation via the inhibition of the MAP-Kinase pathway while preserving the NF-kB pathway (important in immune vigilance). Rytvela has been shown to inhibit inflammatory upregulation and uterine activation while preserving fetal development.
Objectives:
The study aimed to further pre-clinical development of rytvela by evaluating its optimal dose and minimal duration of treatment to inhibit the inflammatory cascade, prolong gestation and promote neonatal outcome.
Study design:
Pregnant CD-1 mice were injected with LPS (10 ug i.p.) or interleukin-1 (1 ug/kg i.u.) on gestational day 16 to induce preterm labor. Rytvela was injected at different doses (0.1, 0.5, 1, 2, 4 mg/kg/day s.c.) from gestational day 16 to 19. To evaluate the minimal duration of treatment, mice were injected with Rytvela (2 mg/kg/day s.c.) over the course of 24, 36 or 48 hours. Rate of prematurity (gestational day<18.5) and neonate survival and weight were evaluated. Gestational tissues were collected at gestational day 17.5 to quantify cytokines, pro-inflammatory mediators, and uterine activating proteins by RT-qPCR and ELISA. Neonatal lungs and intestines were collected from postnatal day 5 to 7 and analyzed by histology.
Results:
Rytvela exhibited a dose-response profile and achieved EMAX at a dose of 2 mg/kg/day by reducing 70% of LPS-induced preterm births as well as 60% of IL-1β-induced preterm births. Rytvela also attained EMAX at a dose of 1 mg/kg/day by increasing neonate survival by up to 65% in both models of preterm birth. Rytvela protects fetuses from inflammatory insult as of 24 hours preserving lung and intestinal integrity and prevents preterm birth and fetal mortality by 60% and 50% respectively as of 36 hours of treatment.
Conclusions:
The EMAX of Rytvela was achieved at 2 mg/kg/day with improved birth outcome and prevented inflammatory upregulation upon (only) 36 hours of treatment. Rytvela exhibits desirable properties for the safe prevention of preterm birth and fetal protection.
