MCT1-mediated transport of valeric acid promotes porcine preimplantation embryo development by improving mitochondrial function and inhibiting the autophagic AMPK-ULK1 pathway.

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality.

Cyclophosphamide reduces gene transcriptional activity and embryo in vitro development by inhibiting NF-κB expression through decreasing AcH4K12.

Cyclophosphamide (CTX), a widely used chemotherapeutic agent for cancer treatment, has been associated with long-term toxicity and detrimental effects on oocytes and ovaries, resulting in female reproductive dysfunction. This study aimed to investigate the potential impact of CTX on in vitro maturation (IVM) injury of porcine oocytes and subsequent embryonic development, as well as its effects on epigenetic modification and gene activation during early embryonic development. The results demonstrated that CTX treatment caused aberrant spindle structure and mitochondrial dysfunction during oocyte maturation, inducing DNA damage and early apoptosis, which consequently disrupted meiotic maturation. Indeed, CTX significantly reduced the in vitro developmental capacity of porcine embryos, and induced DNA damage and apoptosis in in vitro fertilization (IVF) blastocysts. Importantly, CTX induced abnormal histone modification of AcH4K12 in early porcine embryos. Moreover, addition of LBH589 before zygotic genome activation (ZGA) effectively increased AcH4K12 levels and restored the protein expression of NF-κB, which can effectively enhance the in vitro developmental potential of IVF embryos. The DNA damage and apoptosis induced by CTX compromised the quality of the blastocysts, which were recovered by supplementation with LBH589. This restoration was accompanied by down-regulation of BAX mRNA expression and up-regulation of BCL2, POU5F1, SOX2 and SOD1 mRNA expression. These findings indicated that CTX caused abnormal histone modification of AcH4K12 in early porcine embryos and reduced the protein expression of NF-κB, a key regulator of early embryo development, which may block subsequent ZGA processes.

The ginsenoside Rh2 protects porcine oocytes against aging and oxidative stress by regulating SIRT1 expression and mitochondrial activity.

Post-ovulatory aging, a major problem faced by oocytes cultured in vitro, causes oxidative damage and mitochondrial dysfunction in oocytes. The ginsenoside Rh2 is one of the main monomeric components of ginseng, but its effects on porcine oocytes are unknown. In the present study, in vitro aging (IVA) and accelerated induction of aging using H2O2 resulted in DNA damage and an increased incidence of abnormal spindle formation in porcine oocytes. Rh2 supplementation increased the antioxidant capacity, reduced the occurrence of early apoptosis, and improved the development of in vitro fertilized blastocysts. It also rescued the abnormal aggregation of mitochondria and the decrease of the mitochondrial membrane potential under mitochondrial dysfunction. Meanwhile, Rh2 enhanced mRNA expression of the anti-aging and mitochondrial biogenesis-related genes silent information regulator of transcription 1 (SIRT1) and peroxisome proliferator-activated receptor coactivator 1-α (PGC-1α), and the antioxidant gene superoxide dismutase 1 (SOD1). The protection of porcine oocytes against aging and oxidative stress by Rh2 was confirmed using the SIRT1-specific inhibitor EX-527. Our results reveal that Rh2 upregulates SIRT1/PGC-1α to enhance mitochondrial function in porcine oocytes and improve their quality. Our study indicates that Rh2 can be used to prevent mitochondrial dysfunction in oocytes.

Metanetwork Transmission Model for Predicting a Malaria-Control Strategy.

Background: Mosquitoes are the primary vectors responsible for malaria transmission to humans, with numerous experiments having been conducted to aid in the control of malaria transmission. One of the main approaches aims to develop malaria parasite resistance within the mosquito population by introducing a resistance (R) allele. However, when considering this approach, some critical factors, such as the life of the mosquito, female mosquito fertility capacity, and human and mosquito mobility, have not been considered. Thus, an understanding of how mosquitoes and humans affect disease dynamics is needed to better inform malaria control policymaking. Methods: In this study, a method was proposed to create a metanetwork on the basis of the geographic maps of Gambia, and a model was constructed to simulate evolution within a mixed population, with factors such as birth, death, reproduction, biting, infection, incubation, recovery, and transmission between populations considered in the network metrics. First, the same number of refractory mosquitoes (RR genotype) was introduced into each population, and the prevalence of the R allele (the ratio of resistant alleles to all alleles) and malaria were examined. In addition, a series of simulations were performed to evaluate two different deployment strategies for the reduction of the prevalence of malaria. The R allele and malaria prevalence were calculated for both the strategies, with 10,000 refractory mosquitoes deployed into randomly selected populations or selection based on nodes with top-betweenness values. The 10,000 mosquitoes were deployed among 1, 5, 10, 20, or 40 populations. Results: The simulations in this paper showed that a higher RR genotype (resistant-resistant genes) ratio leads to a higher R allele prevalence and lowers malaria prevalence. Considering the cost of deployment, the simulation was performed with 10,000 refractory mosquitoes deployed among 1 or 5 populations, but this approach did not reduce the original malaria prevalence. Thus, instead, the 10,000 refractory mosquitoes were distributed among 10, 20, or 40 populations and were shown to effectively reduce the original malaria prevalence. Thus, deployment among a relatively small fraction of central nodes can offer an effective strategy to reduce malaria. Conclusion: The standard network centrality measure is suitable for planning the deployment of refractory mosquitoes. Importance: Malaria is an infectious disease that is caused by a plasmodial parasite, and some control strategies have focused on genetically modifying the mosquitoes. This work aims to create a model that takes into account mosquito development and malaria transmission among the population and how these factors influence disease dynamics so as to better inform malaria-control policymaking.