Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development

Pathogens comprised of viruses, bacteria, gut microbiome, and parasites are a leading cause of ever-emerging diseases in humans. Studying pathogens for their ability to cause diseases is a topic of critical discussion among scientists and pharmaceutical centers for effective drug development that diagnose, treat, and prevent infection-associated disorders. Pathogens impact health either directly by invading the host or by eliciting an acute inflammatory immune response. This paradigm of inflammatory immune responses is even more consequential in people who may be immunocompromised. In this regard, pregnancy offers an altered immunity scenario, which may allow the onset of severe diseases. Viruses, such as Influenza, HIV, and now SARS-CoV-2, associated with the COVID-19 pandemic, raise new concerns for maternal and fetal/neonatal health. Intrauterine bacterial and parasitic infections are also known to impact pregnancy outcomes and neonatal health. More importantly, viral and bacterial infections during pregnancy have been identified as a common contributor to fetal brain development defects. Infection-mediated inflammatory uterine immune milieu is thought to be the main trigger for causing poor fetal brain development, resulting in long-term cognitive impairments. The concept of in utero programming of childhood and adult disorders has revolutionized the field of neurodevelopment and its associated complications. Recent findings in mice and humans clearly support the idea that uterine immunity during pregnancy controls the health trajectory of the child and considerably influences the cognitive function and mental health. In this review, we focus on the in utero programming of autism spectrum disorders (ASD) and assess the effects of pathogens on the onset of ASD-like symptoms

Effects of Transient Hypoxia versus Prolonged Hypoxia on Satellite Cell Proliferation and Differentiation In Vivo

The microenvironment of the injury site can have profound effects on wound healing. Muscle injury results in ischemia leading to short-termlocal hypoxia, but there are conflicting reports on the role of hypoxia on themyogenic programin vivo and in vitro. In our rat model of mitochondrial restoration (MR), temporary upregulation of mitochondrial activity by a cocktail of organelle-encoded RNAs results in satellite cell proliferation and initiation ofmyogenesis.We now report thatMR leads to a transient hypoxic response in situ. Inhibition of hypoxia by lowering mitochondrial O2 consumption, either by respiratory electron transport inhibitors, or by NO-mediated inhibition of O2 binding to cytochrome c oxidase, resulted in exacerbation of inflammation. Lentivirus-mediated knockdown of hypoxia-inducible factor

RNA-Mediated Restoration of Mitochondrial Function in Cells Harboring a Kearns Sayre Syndrome Mutation.

Mutations in mitochondrial DNA (mtDNA) generate multi-system disorders due to failure of ATP production. A cybrid containing a 1.9-kb mtDNA deletion from a patient with Kearns Sayre Syndrome is respirationdefective and grows glycolytically. When treated with a ribonucleoprotein (RNP) complex of polycistronic RNA 1 (pcRNA1) containing mtDNA-encoded genes and a multi-subunit carrier complex R8, full-length pcRNA1 was transported to mitochondria. Translation of the pcRNA1-encoded mRNAs was observed in mitochondria from RNP-treated cells. Respiration of the cybrid was rescued to ~90% of normal within hours, switching the cells to aerobic growth. These findings have implications for the development of effective mitochondrial gene therap

Modulation of Mitochondrial Respiratory Capacity by Carrier-Mediated Transfer of RNA in Vivo

Genetic dysfunction of mitochondria is pathological, but an effective method of nucleic acid delivery to mitochondria in vivo is lacking. Injection into rodents of tagged polycistronic RNAs (pcRNAs) encoding parts of the organelle genome and bound to a carrier complex, resulted in rapid uptake and concentration of the RNA in many tissues. The delivered RNA was localized to mitochondria. A pan-genomic cocktail of pcRNAs restored mRNA levels, stimulated mitochondrial translation and respiratory capacity of skeletal muscle of middle-aged and old rats. Thus, the carrier-based protocol may be suitable for delivery of functional RNAs to mitochondria in vivo

CIDEA Transcriptionally Regulates UCP1 for Britening and Thermogenesis in Human Fat Cells

© 2019 The Author(s) Our study identifies a transcriptional role of cell death-inducing DNA fragmentation factor-like effector A (CIDEA), a lipid-droplet-associated protein, whereby it regulates human adipocyte britening/beiging with consequences for the regulation of energy expenditure. The comprehensive transcriptome analysis revealed CIDEA\u27s control over thermogenic function in brite/beige human adipocytes. In the absence of CIDEA, achieved by the modified dual-RNA-based CRISPR-Cas9nD10A system, adipocytes lost their britening capability, which was recovered upon CIDEA re-expression. Uncoupling protein 1 (UCP1), the most upregulated gene in brite human adipocytes, was suppressed in CIDEA knockout (KO) primary human adipocytes. Mechanistically, during induced britening, CIDEA shuttled from lipid droplets to the nucleus via an unusual nuclear bipartite signal in a concentration-dependent manner. In the nucleus, it specifically inhibited LXRα repression of UCP1 enhancer activity and strengthened PPARγ binding to UCP1 enhancer, hence driving UCP1 transcription. Overall, our study defines the role of CIDEA in increasing thermogenesis in human adipocytes

Rosiglitazone remodels the lipid droplet and britens human visceral and subcutaneous adipocytes ex vivo

Copyright © 2019 Lee et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Treatment with PPAR agonists in vivo improves human adipocyte metabolism, but the cellular mechanisms and possible depot differences in responsiveness to their effects are poorly understood. To examine the ex vivo metabolic effects of rosiglitazone (Rosi), we cultured explants of human visceral (omental) and abdominal subcutaneous adipose tissues for 7 days. Rosi increased mRNA levels of transcriptional regulators of brite/beige adipocytes (PGC1, PRDM16), triglyceride synthesis (GPAT3, DGAT1), and lipolysis (ATGL) similarly in adipose tissues from both depots. In parallel, Rosi increased key modulators of FA oxidation (UCP1, FABP3, PLIN5 protein), rates of FA oxidation, and protein levels of electron transport complexes, suggesting an enhanced respiratory capacity as confirmed in newly differentiated adipocytes. Rosi led to the formation of small lipid droplets (SLDs) around the adipocyte central lipid droplet; each SLD was decorated with redistributed mitochondria that colocalized with PLIN5. SLD maintenance required lipolysis and FA reesterification. Rosi thus coordinated a structural and metabolic remodeling in adipocytes from both visceral and subcutaneous depots that enhanced oxidative capacity. Selective targeting of these cellular mechanisms to improve adipocyte FA handling may provide a new approach to treat metabolic complications of obesity and diabetes

Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia

We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia–reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy–lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs. H/R-induced accumulation of protein aggregates follows a similar pattern that occurs in PHTs treated with a lysosomal disruptor, chloroquine. Importantly, the placenta from early-onset PE deliveries exhibits the same features as seen in H/R-treated PHTs. Taken together, our results indicate that H/R disrupts autophagic machinery in PHTs and that impaired autophagy in the placenta from early-onset PE deliveries mimics the events in H/R-treated PHTs. Notably, assessment of key regulators at each stage of autophagic processes, especially lysosomal integrity, and verification of autophagic ultrastructure are essential for an accurate evaluation of autophagy activity in human trophoblasts and placental tissue from PE deliveries

Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia

Abstract Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer’s and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing. Here we find significant cis P-tau in the placenta and serum of PE patients, and in primary human trophoblasts exposed to hypoxia or sera from PE patients due to Pin1 inactivation. Depletion of cis P-tau from PE patient sera by the antibody prevents their ability to disrupt trophoblast invasion and endovascular activity and to cause the PE-like pathological and clinical features in pregnant humanized tau mice. Our studies uncover that cis P-tau is a central circulating etiological driver and its stereo-specific antibody is valuable for early PE diagnosis and treatment

Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication