The potential role of viral priming in bacterial induced preterm labour, and 15dPGJ2 in its prevention

Introduction: Preterm labour occurs in 10% of pregnancies and is a major contributor of neonatal morbidity and mortality. Bacterial-induced preterm labour is thought to contribute to up to 40% of preterm births. However, evidence is mounting for the role of viruses in preterm labour with a ‘double-hit’ of both a viral and bacterial insult during pregnancy increasing susceptibility to bacterial-induced preterm labour. The transcription factors NF-κB and AP-1 are important in regulating key mediators for labour and are activated by the recognition of the toll-like receptors (TLRs) to invading microorganisms. The use of an anti-inflammatory 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) has been shown to successfully inhibit IL-1β-induced NF-κB activation and delay preterm labour in a murine model of inflammation-induced preterm labour. Aims: The effect of ‘double-hit’ in human gestational tissue using in vitro models of ascending and haematogenous spread of infection was studied. 15dPGJ2 as an anti-inflammatory agent in a solid lipid nanoparticle form is investigated. Methods: Vaginal epithelial cells (VEC), amniocytes and myocytes were used as an in vitro model of ascending infection and placental explants and PBMC were used as an in vitro model of systemic infection. PCR, RT-QPCR were used for examining TLR expression. Western immunoblotting was used to detect phospho-p65, phospho-c-Jun and phospho-IRF3. ELISAs were used to examine cytokine, chemokine and PGE2 production. Results: Gestational tissues expressed all TLRs with the exception of vaginal epithelial cells which lacked TLR4 mRNA. TLR3 protein was detected and further induced with poly I:C (TLR3 agonist) stimulation in vaginal epithelial cells (VEC), amniocytes, myocytes, PBMC and placental explants. In the ascending infection model, local TLR3 priming prior to TLR4 and TLR2/6 stimulation augmented cytokine, chemokine and PGE2 production in amniocytes and myocytes compared to treatment with the individual ligand alone. In VECs, only TLR2/6 (following TLR3 priming) showed augmented pro-inflammatory cytokine and PGE2 production. In the haematogenous infection model, local TLR3 priming prior to TLR2 and 2/6 stimulation augmented pro- and anti-inflammatory, chemokines, and PGE2 production in PBMCs. In placental explants, only chemokines and IL-10 production were augmented. However, culturing fresh placental explants with TLR3-primed and TLR2-treated media derived from the PBMCs priming experiment led to augmented IL-6 and IL-8 production. Poly I:C stimulation alone increased the expression of TLR3 and TLR2 and phospho-IRF3 protein. The 15dPGJ2-loaded SLN failed to inhibit IL-1β induced NF-κB and AP-1. Conclusion: A ‘double-hit’ of viral and bacterial stimuli leads to an augmented pro-inflammatory response in human gestational tissue, with the greatest and most consistent effect seen with TLR3 priming prior to TLR2/6 agonist stimulation. It is possible that this is due to augmented activation of phospho-IRF3 and TLR3 mediated increased expression of the TLR2 receptor. These findings should alert us to the potential additive risk of preterm labour in women exposed to viruses in pregnancy. Whilst no anti-inflammatory effect was demonstrated with the 15dPGJ2-loaded SLN.Open Acces

Autologous Human Mesenchymal Stem Cell-Based Therapy in Infertility: New Strategies and Future Perspectives

Infertility could be associated with a few factors including problems with physical and mental health, hormonal imbalances, lifestyles, and genetic factors. Given that there is a concern about the rise of infertility globally, increased focus has been given to its treatment for the last several decades. Traditional assisted reproductive technology (ART) has been the prime option for many years in solving various cases of infertility; however, it contains significant risks and does not solve the fundamental problem of infertility such as genetic disorders. Attention toward the utilization of MSCs has been widely regarded as a promising option in the development of stem-cell-based infertility treatments. This narrative review briefly presents the challenges in the current ART treatment of infertility and the various potential applications of autologous MSCs in the treatment of these reproductive diseases

SARS-CoV-2 genomic surveillance in Malaysia: displacement of B.1.617.2 with AY lineages as the dominant Delta variants and the introduction of Omicron during the fourth epidemic wave

Objectives: This study reported SARS-CoV-2 whole genome sequencing results from June 2021 to January 2022 from seven genome sequencing centers in Malaysia as part of the national surveillance program. Methods: COVID-19 samples that tested positive by reverse transcription polymerase chain reaction and with cycle threshold values <30 were obtained throughout Malaysia. Sequencing of SARS-CoV-2 complete genomes was performed using Illumina, Oxford Nanopore, or Ion Torrent platforms. A total of 6163 SARS-CoV-2 complete genome sequences were generated over the surveillance period. All sequences were submitted to the Global Initiative on Sharing All Influenza Data database. Results: From June 2021 to January 2022, Malaysia experienced the fourth wave of COVID-19 dominated by the Delta variant of concern, including the original B.1.617.2 lineage and descendant AY lineages. The B.1.617.2 lineage was identified as the early dominant circulating strain throughout the country but over time, was displaced by AY.59 and AY.79 lineages in Peninsular (west) Malaysia, and the AY.23 lineage in east Malaysia. In December 2021, pilgrims returning from Saudi Arabia facilitated the introduction and spread of the BA.1 lineage (Omicron variant of concern) in the country. Conclusion: The changing trends of circulating SARS-CoV-2 lineages were identified, with differences observed between west and east Malaysia. This initiative highlighted the importance of leveraging research expertise in the country to facilitate pandemic response and preparedness