Hepatocyte Adenosine Kinase Promotes Excessive Fat Deposition and Liver Inflammation.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease is highly associated with obesity and progresses to nonalcoholic steatohepatitis when the liver develops overt inflammatory damage. While removing adenosine in the purine salvage pathway, adenosine kinase (ADK) regulates methylation reactions. We aimed to study whether hepatocyte ADK functions as an obesogenic gene/enzyme to promote excessive fat deposition and liver inflammation. METHODS: Liver sections of human subjects were examined for ADK expression using immunohistochemistry. Mice with hepatocyte-specific ADK disruption or overexpression were examined for hepatic fat deposition and inflammation. Liver lipidomics, hepatocyte RNA sequencing (RNA-seq), and single-cell RNA-seq for liver nonparenchymal cells were performed to analyze ADK regulation of hepatocyte metabolic responses and hepatocyte-nonparenchymal cells crosstalk. RESULTS: Whereas patients with nonalcoholic fatty liver disease had increased hepatic ADK levels, mice with hepatocyte-specific ADK disruption displayed decreased hepatic fat deposition on a chow diet and were protected from diet-induced excessive hepatic fat deposition and inflammation. In contrast, mice with hepatocyte-specific ADK overexpression displayed increased body weight and adiposity and elevated degrees of hepatic steatosis and inflammation compared with control mice. RNA-seq and epigenetic analyses indicated that ADK increased hepatic DNA methylation and decreased hepatic Ppara expression and fatty acid oxidation. Lipidomic and single-cell RNA-seq analyses indicated that ADK-driven hepatocyte factors, due to mitochondrial dysfunction, enhanced macrophage proinflammatory activation in manners involving increased expression of stimulator of interferon genes. CONCLUSIONS: Hepatocyte ADK functions to promote excessive fat deposition and liver inflammation through suppressing hepatocyte fatty acid oxidation and producing hepatocyte-derived proinflammatory mediators. Therefore, hepatocyte ADK is a therapeutic target for managing obesity and nonalcoholic fatty liver disease.

FoxO1 Deficiency Enhances Cell Proliferation and Survival Under Normoglycemia and Promotes Angiogenesis Under Hyperglycemia in the Placenta.

FoxO1 is an important transcriptional factor that regulates cell survival and metabolism in many tissues. Deleting FoxO1 results in embryonic death due to failure of chorioallantoic fusion at E8.5; however, its role in placental development during mid-late gestation is unclear. In both human patients with gestational diabetes and pregnant mice with hyperglycemia, placental FoxO1 expression was significantly increased. Using FoxO1+/- mice, the effects of FoxO1 haploinsufficiency on placental development under normoglycemia and hyperglycemia were investigated. With FoxO1 haploinsufficiency, the term placental weight increased under both normal and hyperglycemic conditions. Under normoglycemia, this weight change was associated with a general enlargement of the labyrinth, along with increased cell proliferation, decreased cell apoptosis, and decreased expression of p21, p27, Casp3, Casp8, and Rip3. However, under hyperglycemia, the placental weight change was associated with increased fetal blood space, VEGFA overexpression, and expression changes of the angiogenic markers, Eng and Tsp1. In conclusion, FoxO1 plays a role in regulating cell proliferation, cell survival, or angiogenesis, depending on blood glucose levels, during placenta development.

Tbx5 inhibits hedgehog signaling in determination of digit identity.

Dominant TBX5 mutation causes Holt-Oram syndrome (HOS), which is characterized by limb defects in humans, but the underlying mechanistic basis is unclear. We used a mouse model with Tbx5 conditional knockdown in Hh-receiving cells (marked by Gli1+) during E8 to E10.5, a previously established model to study atrial septum defects, which displayed polydactyly or hypodactyly. The results suggested that Tbx5 is required for digit identity in a subset of limb mesenchymal cells. Specifically, Tbx5 deletion in this cell population decreased cell apoptosis and increased the proliferation of handplate mesenchymal cells. Furthermore, Tbx5 was found to negatively regulate the Hh-signaling activity through transcriptional regulation of Ptch1, a known Hh-signaling repressor. Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb defects, thus placing Tbx5 upstream of Hh-signaling in limb defects. This work reveals an important missing component necessary for understanding not only limb development but also the molecular and genetic mechanisms underlying HOS.

Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development.

Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), were known to cause outflow tract (OFT) defects in both human and mouse, but the underlying molecular mechanism was not clear. In this study, Gata4 haploinsufficiency in mice was found to result in OFT defects including double outlet right ventricle (DORV) and ventricular septum defects (VSDs). Gata4 was shown to be required for Hedgehog (Hh)-receiving progenitors within the second heart field (SHF) for normal OFT alignment. Restored cell proliferation in the SHF by knocking-down Pten failed to rescue OFT defects, suggesting that additional cell events under Gata4 regulation is important. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion, which is associated with abnormal EMT and cell proliferation in Gata4 haploinsufficiency. The genetic interaction of Hh signaling and Gata4 is further demonstrated to be important for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA). Restoration of Hedgehog signaling renormalized SHF cell proliferation and migration, and rescued OFT defects in Gata4 haploinsufficiency. In addition, there was enhanced Gata6 expression in the SHF of the Gata4 heterozygotes. The Gata4-responsive repressive sites were identified within 1kbp upstream of the transcription start site of Gata6 by both ChIP-qPCR and luciferase reporter assay. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development.

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.

Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease.

Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/-) male mice were examined for liver injuries. Osr1+/- mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/- mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/- liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/- liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/- and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.

Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. METHODS: Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. RESULTS: The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. CONCLUSIONS: Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.

Celastrol alleviates metabolic disturbance in high-fat diet-induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation.

Celastrol, a natural triterpene, has been shown to treat obesity and its related metabolic disorders. In this study, we first assessed the relationship between the antiobesity effects of celastrol and its antiinflammatory activities. Our results showed that celastrol can reduce weight gain, ameliorate glucose intolerance, insulin resistance, and dyslipidemia without affecting food intake in high-fat diet-induced obese mice. A CLAMS was used to clarify the improvement of metabolic profiles was attribute to increased adipose thermogenesis after celastrol treatment. Further studies found that celastrol decreased the infiltration of macrophage as well as its inflammatory products (IL-1ß, IL-18, MCP-1α, and TNF-α) in liver and adipose tissues, which also displayed an obvious inhibition of TLR3/NLRP3 inflammasome molecules. This study demonstrated that celastrol could be a potential drug for treating metabolic disorders, the underlying mechanism is related to ameliorating metabolic inflammation, thus increasing body energy expenditure.

Maternal diet intervention before pregnancy primes offspring lipid metabolism in liver.

Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children.

Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation.

GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs. Gata4 mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream of Hh components: Gata4 activated a cis-regulatory element at Gli1 in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged in Smoothened mutants, and Hh pathway genes were unchanged in Pten mutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominant Gata4 mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.

Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero.

Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of ß-catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice.

Correction: Foxf Genes Integrate Tbx5 and Hedgehog Pathways in the Second Heart Field for Cardiac Septation.

[This corrects the article DOI: 10.1371/journal.pgen.1004604.].

Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation.

Atrial septal defects (ASDs) are a common human congenital heart disease (CHD) that can be induced by genetic abnormalities. Our previous studies have demonstrated a genetic interaction between Tbx5 and Osr1 in the second heart field (SHF) for atrial septation. We hypothesized that Osr1 and Tbx5 share a common signaling networking and downstream targets for atrial septation. To identify this molecular networks, we acquired the RNA-Seq transcriptome data from the posterior SHF of wild-type, Tbx5(+/) (-), Osr1(+/-), Osr1(-/-) and Tbx5(+/-)/Osr1(+/-) mutant embryos. Gene set analysis was used to identify the Kyoto Encyclopedia of Genes and Genomes pathways that were affected by the doses of Tbx5 and Osr1. A gene network module involving Tbx5 and Osr1 was identified using a non-parametric distance metric, distance correlation. A subset of 10 core genes and gene-gene interactions in the network module were validated by gene expression alterations in posterior second heart field (pSHF) of Tbx5 and Osr1 transgenic mouse embryos, a time-course gene expression change during P19CL6 cell differentiation. Pcsk6 was one of the network module genes that were linked to Tbx5. We validated the direct regulation of Tbx5 on Pcsk6 using immunohistochemical staining of pSHF, ChIP-quantitative polymerase chain reaction and luciferase reporter assay. Importantly, we identified Pcsk6 as a novel gene associated with ASD via a human genotyping study of an ASD family. In summary, our study implicated a gene network involving Tbx5, Osr1 and Pcsk6 interaction in SHF for atrial septation, providing a molecular framework for understanding the role of Tbx5 in CHD ontogeny.

Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation.

RATIONALE: Mutations of TBX5 cause Holt-Oram syndrome (HOS) in humans, a disease characterized by atrial or occasionally ventricular septal defects in the heart and skeletal abnormalities of the upper extremity. Previous studies have demonstrated that Tbx5 regulates Osr1 expression in the second heart field (SHF) of E9.5 mouse embryos. However, it is unknown whether and how Tbx5 and Osr1 interact in atrial septation. OBJECTIVE: To determine if and how Tbx5 and Osr1 interact in the posterior SHF for cardiac septation. METHODS AND RESULTS: In the present study, genetic inducible fate mapping showed that Osr1-expressing cells contribute to atrial septum progenitors between E8.0 and E11.0. Osr1 expression in the pSHF was dependent on the level of Tbx5 at E8.5 and E9.5 but not E10.5, suggesting that the embryo stage before E10.5 is critical for Tbx5 interacting with Osr1 in atrial septation. Significantly more atrioventricular septal defects (AVSDs) were observed in embryos with compound haploinsufficiency for Tbx5 and Osr1. Conditional compound haploinsufficiency for Tbx5 and Osr1 resulted in a significant cell proliferation defect in the SHF, which was associated with fewer cells in the G2 and M phases and a decreased level of Cdk6 expression. Remarkably, genetically targeted disruption of Pten expression in atrial septum progenitors rescued AVSDs caused by Tbx5 and Osr1 compound haploinsufficiency. There was a significant decrease in Smo expression, which is a Hedgehog (Hh) signaling pathway modulator, in the pSHF of Osr1 knockout embryos at E9.5, implying a role for Osr1 in regulating Hh signaling. CONCLUSIONS: Tbx5 and Osr1 interact to regulate posterior SHF cell cycle progression for cardiac septation.

A Study on the Borehole Wall Stability Analysis and Slurry Ratio Optimization for Construction of Pile in Complex Marine Strata.

In order to address the issue of hole collapse, which frequently arises when boring piles are being constructed in intricate marine strata, this paper discusses the influence of the slurry ratio on the slurry performance as well as the mechanism of slurry wall protection. It performs this by means of theoretical analysis, laboratory ratio testing, engineering analogies, numerical simulation, and field testing. Our findings demonstrate that adding sodium polyacrylate and sodium carboxymethyl cellulose can enhance mud's viscosity, contribute to flocculation, and improve the connection between mud and soil layers. Refering similar engineering cases, three optimization schemes are proposed for achieving a mud ratio that offers wall protection in complex marine strata. Furthermore, the particle flow model of slurry viscous fluid is established. The collapse of holes in the sand layer is reflected in the uneven radial displacement of hole walls and the invasion of mud particles. Increasing the viscosity of mud gradually transforms the uneven radial deformation of pore walls in the sand layer into a uniform radial deformation, whereas increasing the proportion of mud significantly decreases the radial displacement of hole walls. Additionally, when the mud pressure in the hole is 300 kPa and 600 kPa, the wall protection effect is better, and there is no particle penetration by substances such as sand. It is found that a high mud pressure can promote the diffusion of mud particles into the sand layer, while low mud pressure cannot balance the pressure on deep soil. The results of the field tests show that the ratio of water-clay-bentonite-CMC-Na-sodium carbonate = 700:110:90:1.5:0.5 used (where the mass percentage of each material is 77.8% water, 12.2% clay, 10% bentonite, 0.16% CMC-Na, and 0.05% sodium carbonate) can effectively prevent hole collapse and reduce the thickness of the sand layer at the bottom of the hole by 50%.

Experiment and Analysis of Variance for Stabilizing Fine-Grained Soils with Cement and Sawdust Ash as Liner Materials.

Due to volume change and low strength, fine-grained soils are problematic in construction. Stabilization with cement and sawdust ash (SDA) by-products can improve engineering properties. This study aimed to investigate the effectiveness of cement and sawdust ash (SDA) in stabilizing fine-grained soils for liner applications. Varying proportions of cement (0-9%) and SDA (0-10%) were added to soil samples (n = 24). Specimens were tested for unconfined compressive strength (UCS), hydraulic conductivity (HC), and volumetric shrinkage strain (VSS). Two-way ANOVA analyzed stabilization effects. Optimal stabilization occurred with 6% cement and 6% SDA, resulting in significant increases in UCS (51 to 375 kN/m2) and decreases in HC (1.7 × 10-8 to 4.7 × 10-10 m/s) and VSS (12.8 to 3.51%) compared to untreated soil. ANOVA indicated that both cement and SDA had statistically significant (p < 0.05) effects on improving all three engineering properties. The addition of 6% cement and 6% SDA significantly improved the expansive soil's strength, hydraulic conductivity, and volume change properties. ANOVA confirmed the quantitative improvements and the significance of both stabilizers. Stabilization using the by-product SDA has the potential to be a sustainable soil improvement method.

Nutrition and Supplements during Pregnancy: A Vital Component in Building the Health and Well-Being of Both the Mother and the Developing Baby.

Maternal health is of the utmost importance during pregnancy, not just for the mother but also for the developing fetus [...].

The inter- and multi- generational epigenetic alterations induced by maternal cadmium exposure.

Exposure to cadmium during pregnancy, from environmental or lifestyle factors, has been shown to have detrimental fetal and placental developmental effects, along with negatively impacting maternal health during gestation. Additionally, prenatal cadmium exposure places the offspring at risk for developing diseases in infancy, adolescence, and adulthood. Although given much attention, the underlying mechanisms of cadmium-induced teratogenicity and disease development remain largely unknown. Epigenetic changes in DNA, RNA and protein modifications have been observed during cadmium exposure, which implies a scientific premise as a conceivable mode of cadmium toxicity for developmental origins of health and disease (DOHaD). This review aims to examine the literature and provide a comprehensive overview of epigenetic alterations induced by prenatal cadmium exposure, within the developing fetus and placenta, and the continued effects observed in childhood and across generations.

Trophoblast Differentiation: Mechanisms and Implications for Pregnancy Complications.

Placental development is a tightly controlled event, in which cell expansion from the trophectoderm occurs in a spatiotemporal manner. Proper trophoblast differentiation is crucial to the vitality of this gestational organ. Obstructions to its development can lead to pregnancy complications, such as preeclampsia, fetal growth restriction, and preterm birth, posing severe health risks to both the mother and offspring. Currently, the only known treatment strategy for these complications is delivery, making it an important area of research. The aim of this review was to summarize the known information on the development and mechanistic regulation of trophoblast differentiation and highlight the similarities in these processes between the human and mouse placenta. Additionally, the known biomarkers for each cell type were compiled to aid in the analysis of sequencing technologies.

Understanding PPARγ and Its Agonists on Trophoblast Differentiation and Invasion: Potential Therapeutic Targets for Gestational Diabetes Mellitus and Preeclampsia.

The increasing incidence of pregnancy complications, particularly gestational diabetes mellitus (GDM) and preeclampsia (PE), is a cause for concern, as they can result in serious health consequences for both mothers and infants. The pathogenesis of these complications is still not fully understood, although it is known that the pathologic placenta plays a crucial role. Studies have shown that PPARγ, a transcription factor involved in glucose and lipid metabolism, may have a critical role in the etiology of these complications. While PPARγ agonists are FDA-approved drugs for Type 2 Diabetes Mellitus, their safety during pregnancy is not yet established. Nevertheless, there is growing evidence for the therapeutic potential of PPARγ in the treatment of PE using mouse models and in cell cultures. This review aims to summarize the current understanding of the mechanism of PPARγ in placental pathophysiology and to explore the possibility of using PPARγ ligands as a treatment option for pregnancy complications. Overall, this topic is of great significance for improving maternal and fetal health outcomes and warrants further investigation.