Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population.

The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C>A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007-5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C>A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C>A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition.

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

GAP-43 closely interacts with BDNF in hippocampal neurons and is associated with Alzheimer's disease progression.

Introduction: Growth-associated protein 43 (GAP-43) is known as a neuronal plasticity protein because it is widely expressed at high levels in neuronal growth cones during axonal regeneration. GAP-43 expressed in mature adult neurons is functionally important for the neuronal communication of synapses in learning and memory. Brain-derived neurotrophic factor (BDNF) is closely related to neurodegeneration and synaptic plasticity during the aging process. However, the molecular mechanisms regulating neurodegeneration and synaptic plasticity underlying the pathogenesis and progression of Alzheimer's disease (AD) still remain incompletely understood. Methods: Remarkably, the expressions of GAP-43 and BDNF perfectly match in various neurons in the Human Brain Atlas database. Moreover, GAP-43 and BDNF are highly expressed in a healthy adults' hippocampus brain region and are inversely correlated with the amyloid beta (Aß), which is the pathological peptide of amyloid plaques found in the brains of patients with AD. Results: These data led us to investigate the impact of the direct molecular interaction between GAP-43 and BDNF in hippocampal neuron fate. In this study, we show that GAP-43 and BDNF are inversely associated with pathological molecules for AD (Tau and Aß). In addition, we define the three-dimensional protein structure for GAP-43 and BDNF, including the predictive direct binding sites via analysis using ClusPro 2.0, and demonstrate that the deprivation of GAP-43 and BDNF triggers hippocampal neuronal death and memory dysfunction, employing the GAP-43 or BDNF knock-down cellular models and 5XFAD mice. Conclusion: These results show that GAP-43 and BDNF are direct binding partners in hippocampal neurons and that their molecular signaling might be potential therapeutic targets for AD.

Association of Polymorphisms in FSHR, INHA, ESR1, and BMP15 with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) refers to two or more unsuccessful in vitro fertilization embryo transfers in the same individual. Embryonic characteristics, immunological factors, and coagulation factors are known to be the causes of RIF. Genetic factors have also been reported to be involved in the occurrence of RIF, and some single nucleotide polymorphisms (SNPs) may contribute to RIF. We examined SNPs in FSHR, INHA, ESR1, and BMP15, which have been associated with primary ovarian failure. A cohort of 133 RIF patients and 317 healthy controls consisting of all Korean women was included. Genotyping was performed by Taq-Man genotyping assays to determine the frequency of the following polymorphisms: FSHR rs6165, INHA rs11893842 and rs35118453, ESR1 rs9340799 and rs2234693, and BMP15 rs17003221 and rs3810682. The differences in these SNPs were compared between the patient and control groups. Our results demonstrate a decreased prevalence of RIF in subjects with the FSHR rs6165 A>G polymorphism [AA vs. AG adjusted odds ratio (AOR) = 0.432; confidence interval (CI) = 0.206-0.908; p = 0.027, AA+AG vs. GG AOR = 0.434; CI = 0.213-0.885; p = 0.022]. Based on a genotype combination analysis, the GG/AA (FSHR rs6165/ESR1 rs9340799: OR = 0.250; CI = 0.072-0.874; p = 0.030) and GG-CC (FSHR rs6165/BMP15 rs3810682: OR = 0.466; CI = 0.220-0.987; p = 0.046) alleles were also associated with a decreased RIF risk. Additionally, the FSHR rs6165GG and BMP15 rs17003221TT+TC genotype combination was associated with a decreased RIF risk (OR = 0.430; CI = 0.210-0.877; p = 0.020) and increased FSH levels, as assessed by an analysis of variance. The FSHR rs6165 polymorphism and genotype combinations are significantly associated with RIF development in Korean women.

Uterine artery embolization for postpartum hemorrhage with placenta accreta spectrum.

BACKGROUND: The reported success rate of uterine artery embolization (UAE) for postpartum hemorrhage (PPH) differs by the cause of bleeding; in some reports, UAE shows less successful results in patients with placenta accreta spectrum (PAS). PURPOSE: To evaluate the outcome of UAE for treating PPH associated with PAS. MATERIAL AND METHODS: From September 2011 to September 2021, 227 patients (mean age = 34.67±4.06 years; age range = 19-47 years) underwent UAE for managing intractable PPH. Patients were divided into two groups: those with PAS (n = 46) and those without PAS (n = 181). Delivery details, embolization details, and procedure-related outcomes were compared between the two groups. P values <0.05 were considered statistically significant. RESULTS: The technical success rate was 96.9% (n = 222) and the clinical success rate was 93.8% (n = 215). There were no significant differences in outcome of UAE between the two patient groups. The technical success rate was 95.7% (n = 44) in patients with PAS and 98.3% (n = 178) in patients without PAS (P = 0.267). The clinical success rate was 91.3% (n = 42) in patients with PAS and 95.6% (n = 173) in patients without PAS (P = 0.269). There were 24 cases of immediate complications, including pelvic pain (n = 20), urticaria (n = 3), and puncture site hematoma (n = 1). No major complication was reported. CONCLUSION: UAE is a safe and effective method to control intractable PPH for patients with or without PAS.

The couple of netrin-1/α-Synuclein regulates the survival of dopaminergic neurons via α-Synuclein disaggregation.

The abnormal accumulation and aggregation of the misfolded α-synuclein protein is the neuropathological hallmark of all α-synucleinopathies, including Parkinson's disease. The secreted proteins known as netrins (netrin-1, netrin-3, and netrin-4) are related to laminin and have a role in the molecular pathway for axon guidance and cell survival. Interestingly, only netrin-1 is significantly expressed in the substantia nigra (SN) of healthy adult brains and its expression inversely correlates with that of α-synuclein, which prompted us to look into the role of α-synuclein and netrin-1 molecular interaction in the future of dopaminergic neurons. Here, we showed that netrin-1 and α-synuclein directly interacted in pre-formed fibrils (PFFs) generation test, real time binding assay, and co-immunoprecipitation with neurotoxin treated cell lysates. Netrin-1 deficiency appeared to activate the dopaminergic neuronal cell death signal pathway via α-synuclein aggregation and hyperphosphorylation of α-synuclein S129. Taken together, netrin-1 can be a promising therapeutic molecule in Parkinson's disease. [BMB Reports 2023; 56(2): 126-131].

C/EBPß/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPß from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPß/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPß or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPß/AEP-dependent manner. Hence, our studies demonstrate that C/EBPß/AEP pathway is critical for mediating Lewy body pathology progression in PD.

Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson's disease.

Gut dysbiosis contributes to Parkinson's disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.

Genetic Variations miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G and the Risk of Recurrent Pregnancy Loss in Korean Women

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = 1.520, 95% confidence interval [CI] = 1.038−2.227, p = 0.032; AOR = 2.956, 95% CI = 1.168−7.482, p = 0.022, respectively). Additionally, both miR-499 dominant (AA vs. AG + GG) and recessive (AA + AG vs. GG) models were significantly associated with increased RPL risk (AOR = 1.465, 95% CI = 1.062−2.020, p = 0.020; AOR = 2.677, 95% CI = 1.066−6.725, p = 0.036, respectively). We further propose that miR-10aA>T, miR-30cA>G, and miR-499bA>G polymorphisms effects could contribute to RPL and should be considered during RPL patient evaluation.

The association of maternal serum biomarkers and birth weight in twin pregnancy: a retrospective cohort study.

We retrospectively reviewed the medical records of 524 women with twin pregnancies who underwent antenatal care and gave birth in the past 12 years. Birth weight (BW) data were classified into three groups. We analysed the association between maternal serum biomarkers and BW in twin pregnancies using multiple logistic regression analysis. There were significant differences in the MoM values of pregnancy-associated plasma protein-A (PAPP-A), unconjugated oestriol (uE3) and inhibin A between low BW and healthy newborns. The inhibin A value was significantly higher in women with small-for-gestational-age (SGA) foetuses and the PAPP-A, and uE3 values were lower in the SGA group than in the other groups using the generalised linear mixed model (hierarchical modelling considering cluster effects for twins). Maternal serum biomarkers, including PAPP-A, uE3, and inhibin A, may be associated with SGA in twin pregnancy. Our results might provide useful information for SGA prediction during prenatal period in twin pregnancy. IMPACT STATEMENTWhat is already known on this subject? The SGA is more frequent in twin pregnancies than in singleton, but there is no clearly identification of the aetiology of SGA. Further, most studies have been conducted in singleton pregnancies.What do the results of this study add? The association of each maternal serum marker with SGA was assessed in the current study, and it is demonstrated that the levels of PAPP-A and uE3 in maternal serum of SGA foetuses were significantly lower than those in the other groups. In contrast, the levels of inhibin A were significantly increased in the SGA.What are the implications of these findings for clinical practice and/or further research? The maternal serum biomarker of inhibin A was a more valuable predictive factor for SGA prediction in twins. The results of this study can be used in counselling prenatal screening. Further prospective research is needed to combine with ultrasound growth parameters, which can be generalised for the prediction of SGA in twins.

Genetic Polymorphisms in the 3'-Untranslated Regions of SMAD5, FN3KRP, and RUNX-1 Are Associated with Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is typically defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation. Although the causes of idiopathic RPL are not completely understood, vascular development and glucose concentration were reported to correlate with the pregnancy loss. The TGF-ß signaling pathway which plays a significant role in pregnancy is activated by the interaction between high glucose and SMAD signaling and affects the vascular cells. SMAD5 and RUNX-1 are involved in the TGF-ß signaling pathway and contribute to advanced glycation end products (AGEs) production and vascular development. FN3KRP, a newly described gene, is also associated with vascular diseases and suggested to relate to AGEs. Therefore, in the present study, we investigated associations between RPL risk and genetic polymorphisms of SMAD5, FN3KRP, and RUNX-1 in 388 women with RPL and 280 healthy control women of Korean ethnicity. Participants were genotyped using real-time polymerase chain reaction and restriction fragment length polymorphism assay to determine the frequency of SMAD5 rs10515478 C>G, FN3KRP rs1046875 G>A, and RUNX-1 rs15285 G>A polymorphisms. We found that women with RPL had lower likelihoods of the FN3KRP rs1046875 AA genotype (adjusted odds ratio (AOR), 0.553; p = 0.010) and recessive model (AOR, 0.631; p = 0.017). Furthermore, combination analysis showed that SMAD5 rs10515478 C>G and FN3KRP rs1046875 G>A mutant alleles were together associated with reduced RPL risk. These findings suggest that the FN3KRP rs1046875 G>A polymorphism has a significant role on the prevalence of RPL in Korean women. Considering that it is the first study indicating a significant association between FN3KRP and pregnancy disease, RPL, our results suggest the need for further investigation of the role of FN3KRP in pregnancy loss.

Association Study between Mucin 4 (MUC4) Polymorphisms and Idiopathic Recurrent Pregnancy Loss in a Korean Population.

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were associated with increased incidence of RPL in three and four or more pregnancy loss patients. The haplotype analyses showed a tendency for the allelic effect including the association of MUC4 rs882605 A and rs1104760 G alleles with increased incidence of RPL. In addition, the MUC4 rs882605 CA/MUC4 rs2258447 CC genotype combination was associated with increased RPL prevalence. The two exonic polymorphisms lead to amino acid changes of protein and may act as pathogenic variants for RPL. In conclusion, the MUC4 rs882605 C>A and MUC4 rs1104760 A>G polymorphisms were associated with the susceptibility of RPL and we considered them as potential biomarkers for RPL.

UNC5C Receptor Proteolytic Cleavage by Active AEP Promotes Dopaminergic Neuronal Degeneration in Parkinson's Disease.

Netrin-1 is a chemotropic cue mediating axon growth and neural migration in neuronal development, and its receptors deletion in colorectal cancer and UNC5s act as dependence receptors regulating neuronal apoptosis. Asparagine endopeptidase (AEP) is an age-dependent protease that cuts human alpha-synuclein (α-Syn) at N103 and triggers its aggregation and neurotoxicity. In the current study, it is reported that UNC5C receptor is cleaved by AEP in Parkinson's disease (PD) and facilitates dopaminergic neuronal loss. UNC5C is truncated by active AEP in human α-SNCA transgenic mice in an age-dependent manner or induced by neurotoxin rotenone. Moreover, UNC5C is fragmented by AEP in PD brains, inversely correlated with reduced netrin-1 levels. Netrin-1 deprivation in primary cultures induces AEP and caspase-3 activation, triggering UNC5C proteolytic fragmentation and enhancing neuronal loss. Noticeably, blocking UNC5C cleavage by AEP attenuates netrin-1 deprivation-elicited neuronal death and motor disorders in netrin flox/flox mice. Overexpression of AEP-truncated UNC5C intracellular fragment strongly elicits α-Syn aggregation and dopaminergic loss, locomotor deficits in α-SNCA transgenic mice. Hence, the findings demonstrate that netrin-1 reduction and UNC5C truncation by AEP contribute to PD pathogenesis.

First-trimester screening model for small-for-gestational-age using maternal clinical characteristics, serum screening markers, and placental volume: prospective cohort study.

OBJECTIVE: To examine predictive value of first trimester placental volume, maternal clinical characteristics, and serum biomarkers in predicting small-for-gestational-age (SGA) singleton pregnancy. METHODS: We conducted a prospective study to determine whether SGA is associated with maternal clinical factors. Between November 2016 to May 2018, 351 women were enrolled. We included pregnant women who underwent an integrated test for aneuploidy screening. Placental volume, maternal clinical characteristics, and maternal serum pregnancy-associated plasma protein A (PAPP-A) levels in the first trimester (at 10+0-13+6 weeks) and maternal serum biomarkers after 15+0-22+6 weeks were measured. We measured the width, height, and thickness of the placenta and calculated the placental volume using an established mathematical formula; then, we analyzed the association between SGA at delivery, estimated placental volume (EPV), maternal clinical characteristics, and maternal serum biomarkers by multiple logistic regression analysis. RESULTS: In this study, 12.3% (43/351) neonates were delivered before 37 weeks of gestation, and the birth weight of 23.6% (83/351) was below the 10th percentile according to gestational age. On multivariate logistic regression, the MSAFP multiples of the median (MoM) showed the strongest association with SGA in singleton pregnancy (p < .01), and the PAPP-A MoM showed a weaker association in the multiple logistic regression than in the univariate regression (p = .0073 and .0068, respectively). Our prediction model using maternal age, maternal smoking, PAPP-A, and EPV achieved an area under the curve of 0.668 in singleton pregnancy. CONCLUSION: During the first trimester, maternal clinical characteristics, serum biomarkers, and EPV may be used for predicting the risk of SGA in singleton pregnancy.

Association of Polymorphisms in Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator (tPA), and Renin (REN) with Recurrent Pregnancy Loss in Korean Women.

Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses prior to 20 weeks of gestational age. Various factors, including immune dysfunction, endocrine disorders, coagulation abnormality, and genetic disorders influence RPL. In particular, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and renin (REN) have important roles in the thrombotic and thrombolytic systems, and abnormal expression of these genes have a reported negative correlation with pregnancy maintenance. Moreover, some polymorphisms of the three genes are related to expression levels and thrombotic disorder. Therefore, we investigated whether polymorphisms of PAI-1, tPA, and REN are linked to RPL. Genotyping of the six polymorphisms (PAI-1 rs11178, rs1050955, tPA rs4646972, rs2020918, REN rs1464816, and rs5707) was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and associations of the polymorphisms with RPL were evaluated by statistical analysis. The polymorphism PAI-1 rs1050955 GA+AA was associated with decreased RPL risk (AOR, 0.528; 95% CI 0.356-0.781; p = 0.001) as was the REN 10795 rs5707 GG genotype (AOR, 0.487; 95% CI 0.301-0.787; p = 0.003). In contrast, the tPA rs4646972 II genotype correlated with increased RPL risk (AOR, 1.606; 95% CI, 1.047-2.463; p = 0.030). This study provides evidence that tPA Alu rs4646972 may contribute to the risk of idiopathic RPL, but PAI-1 12068 rs1050955 and REN 10795 rs5707 are associated with a decreased risk of RPL. Therefore, these alleles may be useful as biomarkers to evaluate the risk of RPL.

Mitochondrial dysfunction triggers the pathogenesis of Parkinson's disease in neuronal C/EBPß transgenic mice.

Respiratory chain complex I deficiency elicits mitochondrial dysfunction and reactive oxidative species (ROS), which plays a crucial role in Parkinson's disease (PD) pathogenesis. However, it remains unclear whether the impairment in other complexes in the mitochondrial oxidative phosphorylation chain is also sufficient to trigger PD onset. Here we show that inhibition of Complex II or III in the electron transport chain (ETC) induces the motor disorder and PD pathologies in neuronal Thy1-C/EBPß transgenic mice. Through a cell-based screening of mitochondrial respiratory chain inhibitors, we identified TTFA (complex II inhibitor) and Atovaquone (complex III inhibitor), which robustly block the oxidative phosphorylation functions, strongly escalate ROS, and activate C/EBPß/AEP pathway that triggers dopaminergic neuronal cell death. Oral administration of these inhibitors to Thy1-C/EBPß mice elicits constipation and motor defects, associated with Lewy body-like inclusions. Deletion of SDHD (Succinate dehydrogenase) gene from the complex II in the Substantia Nigra of Thy1-C/EBPß mice triggers ROS and PD pathologies, resulting in motor disorders. Hence, our findings demonstrate that mitochondrial ETC inactivation triggers PD pathogenesis via activating C/EBPß/AEP pathway.

Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aß production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.

Gut inflammation triggers C/EBPß/δ-secretase-dependent gut-to-brain propagation of Aß and Tau fibrils in Alzheimer's disease.

Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may have originated from the gut, but the mechanism underlying this phenomenon is not fully understood. C/EBPß/δ-secretase signaling in the colon was investigated in a 3xTg AD mouse model in an age-dependent manner. We applied chronic administration of 1% dextran sodium sulfate (DSS) to trigger gut leakage or colonic injection of Aß or Tau fibrils or AD patient brain lysates in 3xTg mice and combined it with excision/cutting of the gut-brain connecting vagus nerve (vagotomy), in order to explore the role of the gut-brain axis in the development of AD-like pathologies and to monitor C/EBPß/δ-secretase signaling under those conditions. We found that C/EBPß/δ-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of Aß and Tau fibrils that spread to the brain. DSS treatment promotes gut leakage and facilitates AD-like pathologies in both the gut and the brain of 3xTg mice in a C/EBPß/δ-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates Aß and Tau pathologies, and restores learning and memory. Aß or Tau fibrils or AD patient brain lysates injected into the colon propagate from the gut into the brain via the vagus nerve, triggering AD pathology and cognitive dysfunction. The results indicate that inflammation activates C/EBPß/δ-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.

Genetic Polymorphisms in miR-604A>G, miR-938G>A, miR-1302-3C>T and the Risk of Idiopathic Recurrent Pregnancy Loss.

The purpose of this study was to investigate whether polymorphisms in five microRNAs (miRNAs), miR-604A>G, miR-608C>G, 631I/D, miR-938G>A, and miR-1302-3C>T, are associated with the risk of idiopathic recurrent pregnancy loss (RPL). Blood samples were collected from 388 patients with idiopathic RPL (at least two consecutive spontaneous abortions) and 227 control participants. We found the miR-604 AG and AG + GG genotypes of miR-604, the miR-938 GA and GA + AA genotypes of miR-938, and the miR-1302-3CT and CT + TT genotypes of miR-1302-3 are less frequent than the wild-type (WT) genotypes, miR-604AA, miR-938GG, and miR-1302-3CC, respectively, in RPL patients. Using allele-combination multifactor dimensionality reduction (MDR) analysis, we found that eight haplotypes conferred by the miR-604/miR-608/miR-631/miR-938/miR-1302-3 allele combination, A-C-I-G-T, A-C-I-A-C, G-C-I-G-C, G-C-I-G-T, G-G-I-G-C, G-G-I-G-T, G-G-I-A-C, G-G-D-G-C, three from the miR-604/miR-631/miR-938/miR-1302-3 allele combination, A-I-G-T, G-I-G-C, G-I-A-T, one from the miR-604/miR-631/miR-1302-3 allele combination, G-I-C, and two from the miR-604/miR-1302-3 allele combination, G-C and G-T, were less frequent in RPL patients, suggesting protective effects (all p < 0.05). We also identified the miR-604A>G and miR-938G>A polymorphisms within the seed sequence of the mature miRNAs and aligned the seed sequences with the 3'UTR of putative target genes, methylenetetrahydrofolate reductase (MTHFR) and gonadotropin-releasing hormone receptor (GnRHR), respectively. We further found that the binding affinities between miR-604/miR-938 and the 3'UTR of their respective target genes (MTHFR, GnRHR) were significantly different for the common (miR-604A, miR-938G) and variant alleles (miR-604G, miR-938A). These results reveal a significant association between the miR-604A>G and miR-938G>A polymorphisms and idiopathic RPL and suggest that miRNAs can affect RPL in Korean women.

C/EBPß/AEP Signaling Regulates the Oxidative Stress in Malignant Cancers, Stimulating the Metastasis.

Solid tumors start as a local disease, but some are capable of metastasizing to the lymph nodes and distant organs. The hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating cancer progression and metastasis. However, the molecular mechanisms mediating the disseminated cancer cell metastasis remain incompletely understood. Here, we show that C/EBPß/AEP signaling that is upregulated in breast cancers mediates oxidative stress and lung metastasis, and inactivation of asparagine endopeptidase (AEP, also known as legumain) robustly regulates breast cancer reactive oxygen species (ROS) and metastasis. AEP, a protease activated in acidic conditions, is overexpressed in numerous types of cancer and promotes metastasis. Employing a breast cancer cell line MDA-MD-231, we show that C/EBPß, an oxidative stress or inflammation-activated transcription factor, and its downstream target AEP mediate ROS production as well as migration and invasion in cancer cells. Deficiency of AEP in the MMTV-PyMT transgenic breast cancer mouse model significantly regulates oxidative stress and suppresses lung metastasis. Administration of an innovative AEP inhibitor substantially mitigates ROS production and cancer metastasis. Hence, our study demonstrates that pharmacologic inhibition of AEP activity might provide a disease-modifying strategy to suppress cancer metastasis.