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氯化钠-35Cl 99 atom % 35Cl; CAS Number: 20510-55-8; Linear Formula: Na35Cl; find Sigma-Aldrich-451940 MSDS, related peer-reviewed papers, technical documents, similar products & more at Sigma-Aldrich

氯化钠-35Cl 99 atom % 35Cl | Sigma-Aldrich

氯化钠-<SUP>35</SUP>Cl

Multidrug-resistant Acinetobacter baumannii isolates, particularly those that produce carbapenemases, are increasingly reported worldwide. The biochemically based Carba NP test, extensively validated for the detection of carbapenemase producers among Enterobacteriaceae and Pseudomonas spp., has been modified to detect carbapenemase production in Acinetobacter spp. A collection of 151 carbapenemase-producing and 69 non-carbapenemase-producing Acinetobacter spp. were tested using the Carba NP test and a modified Carba NP protocol (the CarbAcineto NP test) in this study. The CarbAcineto NP test requires modified lysis conditions and an increased bacterial inoculum compared to those of the original Carba NP test. The Carba NP test detects metallo-β-lactamase producers but failed to detect the production of other carbapenemase types among Acinetobacter spp. In contrast, the newly designed CarbAcineto NP test, which is rapid and reproducible, detects all types of carbapenemases with a sensitivity of 94.7% and a specificity of 100%. This cost-effective technique offers a reliable and affordable technique for identifying carbapenemase production in Acinetobacter spp., which is a marker of multidrug resistance in those species. Its use will facilitate the recognition of these carbapenemases and prevent their spread.

CarbAcineto NP test for rapid detection of carbapenemase-producing Acinetobacter spp.

Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization. Ten tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype. The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.

Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer.

In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.

INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia.

The mammalian target of rapamycin (mTOR) pathway integrates multiple signals and regulates crucial cell functions via the molecular complexes mTORC1 and mTORC2. These complexes are functionally dependent on their raptor (mTORC1) or rictor (mTORC2) subunits. mTOR has been associated with oligodendrocyte differentiation and myelination downstream of the PI3K/Akt pathway, but the functional contributions of individual complexes are largely unknown. We show, by oligodendrocyte-specific genetic deletion of Rptor and/or Rictor in the mouse, that CNS myelination is mainly dependent on mTORC1 function, with minor mTORC2 contributions. Myelin-associated lipogenesis and protein gene regulation are strongly reliant on mTORC1. We found that also oligodendrocyte-specific overactivation of mTORC1, via ablation of tuberous sclerosis complex 1 (TSC1), causes hypomyelination characterized by downregulation of Akt signaling and lipogenic pathways. Our data demonstrate that a delicately balanced regulation of mTORC1 activation and action in oligodendrocytes is essential for CNS myelination, which has practical overtones for understanding CNS myelin disorders.

Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system-based RNA-guided endonuclease (RGEN) has recently emerged as a simple and efficient tool for targeted genome editing. In this study, we showed successful targeted mutagenesis using RGENs in medaka, Oryzias latipes. Somatic and heritable mutations were induced with high efficiency at the targeted genomic sequence on the DJ-1 gene in embryos that had been injected with the single guide RNA (sgRNA) transcribed by a T7 promoter and capped RNA encoding a Cas9 nuclease. The sgRNAs that were designed for the target genomic sequences without the 5' end of GG required by the T7 promoter induced the targeted mutations. This suggests that the RGEN can target any sequence adjacent to an NGG protospacer adjacent motif (PAM) sequence, which occurs once every 8 bp. The off-target alterations at 2 genomic loci harboring double mismatches in the 18-bp targeting sequences were induced in the RGEN-injected embryos. However, we also found that the off-target effects could be reduced by lower dosages of sgRNA. Taken together, our results suggest that CRISPR/Cas-mediated RGENs may be an efficient and flexible tool for genome editing in medaka.

Targeted mutagenesis using CRISPR/Cas system in medaka.

Pore-forming toxins (PFT) are water-soluble proteins that possess the remarkable ability to self-assemble on the membrane of target cells, where they form pores causing cell damage. Here, we elucidate the mechanism of action of the haemolytic protein fragaceatoxin C (FraC), a α-barrel PFT, by determining the crystal structures of FraC at four different stages of the lytic mechanism, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore. The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore also exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of a haemolytic toxin.

Structural basis for self-assembly of a cytolytic pore lined by protein and lipid.

To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing. We performed whole-exome sequencing in 13 SCN1A-negative patients with Dravet syndrome and targeted resequencing in 67 additional patients to identify new genes for this disorder. We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1 in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ∼ 75% of cases. We show that GABRA1 and STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families.

GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.

Ephrins and Eph receptors are involved in the establishment of vertebrate tissue boundaries. The complexity of the system is puzzling, however in many instances, tissues express multiple ephrins and Ephs on both sides of the boundary, a situation that should in principle cause repulsion between cells within each tissue. Although co-expression of ephrins and Eph receptors is widespread in embryonic tissues, neurons, and cancer cells, it is still unresolved how the respective signals are integrated into a coherent output. We present a simple explanation for the confinement of repulsion to the tissue interface: Using the dorsal ectoderm-mesoderm boundary of the Xenopus embryo as a model, we identify selective functional interactions between ephrin-Eph pairs that are expressed in partial complementary patterns. The combined repulsive signals add up to be strongest across the boundary, where they reach sufficient intensity to trigger cell detachments. The process can be largely explained using a simple model based exclusively on relative ephrin and Eph concentrations and binding affinities. We generalize these findings for the ventral ectoderm-mesoderm boundary and the notochord boundary, both of which appear to function on the same principles. These results provide a paradigm for how developmental systems may integrate multiple cues to generate discrete local outcomes.

Variable combinations of specific ephrin ligand/Eph receptor pairs control embryonic tissue separation.

Cervical cancer is the third most common cancer in women worldwide. In the present study, global microRNA profiling for 79 cervical cancer patient samples led to the identification of miR-218 down-regulation in cervical cancer tissues compared to normal cervical tissues. Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence. In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion. Survivin (BIRC5) was subsequently identified as an important cervical cancer target of miR-218 using in silico prediction, mRNA profiling, and quantitative real-time PCR (qRT-PCR). Concordant with miR-218 over-expression, survivin knockdown by siRNA decreased clonogenicity, migration, and invasion. YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo. Our findings demonstrate that the miR-218~survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion, and suggest that the inhibition of survivin could be a potential therapeutic strategy to improve outcome in this disease.

The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer.

C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II.

Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.

Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses.

Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.

The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.

Interest in RNA dysfunction in amyotrophic lateral sclerosis (ALS) recently aroused upon discovering causative mutations in RNA-binding protein genes. Here, we show that extensive down-regulation of miRNA levels is a common molecular denominator for multiple forms of human ALS. We further demonstrate that pathogenic ALS-causing mutations are sufficient to inhibit miRNA biogenesis at the Dicing step. Abnormalities of the stress response are involved in the pathogenesis of neurodegeneration, including ALS. Accordingly, we describe a novel mechanism for modulating microRNA biogenesis under stress, involving stress granule formation and re-organization of DICER and AGO2 protein interactions with their partners. In line with this observation, enhancing DICER activity by a small molecule, enoxacin, is beneficial for neuromuscular function in two independent ALS mouse models. Characterizing miRNA biogenesis downstream of the stress response ties seemingly disparate pathways in neurodegeneration and further suggests that DICER and miRNAs affect neuronal integrity and are possible therapeutic targets.

Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS.

The primary sensory system requires the integrated function of multiple cell types, although its full complexity remains unclear. We used comprehensive transcriptome analysis of 622 single mouse neurons to classify them in an unbiased manner, independent of any a priori knowledge of sensory subtypes. Our results reveal eleven types: three distinct low-threshold mechanoreceptive neurons, two proprioceptive, and six principal types of thermosensitive, itch sensitive, type C low-threshold mechanosensitive and nociceptive neurons with markedly different molecular and operational properties. Confirming previously anticipated major neuronal types, our results also classify and provide markers for new, functionally distinct subtypes. For example, our results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type. We demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types. The resulting catalog illustrates the diversity of sensory types and the cellular complexity underlying somatic sensation.

Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Post-translational modifications (such as ubiquitination) of clock proteins are critical in maintaining the precision and robustness of the evolutionarily conserved circadian clock. Ubiquitination of the core clock transcription factor BMAL1 (brain and muscle Arnt-like 1) has recently been reported. However, it remains unknown whether BMAL1 ubiquitination affects circadian pacemaking and what ubiquitin ligase(s) is involved. Here, we show that activating UBE3A (by expressing viral oncogenes E6/E7) disrupts circadian oscillations in mouse embryonic fibroblasts, measured using PER2::Luc dynamics, and rhythms in endogenous messenger ribonucleic acid and protein levels of BMAL1. Over-expression of E6/E7 reduced the level of BMAL1, increasing its ubiquitination and proteasomal degradation. UBE3A could bind to and degrade BMAL1 in a ubiquitin ligase-dependent manner. This occurred both in the presence and absence of E6/E7. We provide in vitro (knockdown/over-expression in mammalian cells) and in vivo (genetic manipulation in Drosophila) evidence for an endogenous role of UBE3A in regulating circadian dynamics and rhythmic locomotor behaviour. Together, our data reveal an essential and conserved role of UBE3A in the regulation of the circadian system in mammals and flies and identify a novel mechanistic link between oncogene E6/E7-mediated cell transformation and circadian (BMAL1) disruption.

The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor.

Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.

Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.

Hepatocyte growth factor (HGF) receptor, also known as Met, is a member of the receptor tyrosine kinase family. The Met-HGF interaction regulates various signalling pathways involving downstream kinases, such as Akt and Erk. Met activation is implicated in wound healing of tissues via multiple biological responses triggered by the above-mentioned signalling cascade. Here we report the development of artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides by means of the RaPID (random non-standard peptide integrated discovery) system, and dimerize the respective monomers through rational design. These dimeric macrocycles specifically and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. This work suggests our approach for generating dimeric macrocycles as non-protein ligands for cell surface receptors can be useful for developing potential therapeutics with a broad range of potential applications.

Artificial human Met agonists based on macrocycle scaffolds.

Protein kinase A (PKA) hyperactivation causes hereditary endocrine neoplasias; however, its role in sporadic epithelial cancers is unknown. Here, we show that heightened PKA activity in the mammary epithelium generates tumors. Mammary-restricted biallelic ablation of Prkar1a, which encodes for the critical type-I PKA regulatory subunit, induced spontaneous breast tumors characterized by enhanced type-II PKA activity. Downstream of this, Src phosphorylation occurs at residues serine-17 and tyrosine-416 and mammary cell transformation is driven through a mechanism involving Src signaling. The phenotypic consequences of these alterations consisted of increased cell proliferation and, accordingly, expansion of both luminal and basal epithelial cell populations. In human breast cancer, low PRKAR1A/high SRC expression defines basal-like and HER2 breast tumors associated with poor clinical outcome. Together, the results of this study define a novel molecular mechanism altered in breast carcinogenesis and highlight the potential strategy of inhibiting SRC signaling in treating this cancer subtype in humans.

PKA signaling drives mammary tumorigenesis through Src.

Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

氯化钠-³⁵Cl

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