Danggui-Yimucao Herb Pair Can Protect Mice From the Immune Imbalance Caused by Medical Abortion and Stabilize the Level of Serum Metabolites

Unintended pregnancy is a situation that every woman may encounter, and medical abortion is the first choice for women, but abortion often brings many sequelae. Angelica sinensis Radix (Danggui) and Leonuri Herba (Yimucao) are widely used in the treatment of gynecological diseases, which can regulate menstrual disorders, amenorrhea, dysmenorrhea, and promote blood circulation and remove blood stasis, but the mechanism for the treatment of abortion is not clear. We determined the ability of Danggui and Yimucao herb pair (DY) to regulate the Th1/Th2 paradigm by detecting the level of progesterone in the serum and the expression of T-bet and GATA-3 in the spleen and uterus. Then, we detected the level of metabolites in the serum and enriched multiple metabolic pathways. The arachidonic acid pathway can directly regulate the differentiation of Th1/Th2 cells. This may be one of the potential mechanisms of DY in the treatment of abortion.

Plasma Lipidome Acts As Diagnostic Marker and Predictor for Cyclosporin Response in Patients with Aplastic Anemia

Background：The lipid metabolomic profile has been well defined in the pathogenesis and differential diagnosis in patients with different myeloid diseases. However, the role of plasma lipidome was rarely explored, especially in aplastic anemia (AA), a disease which has close connection with lipid metabolism. Methods: Peripheral fasting serum levels of patients newly diagnosed with AA from March 2019 to December 2019 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the serum lipid profiles. Meanwhile, the lipidomes for patients with hypocellular myelodysplastic syndrome (h-MDS) and age and sex matched healthy volunteers were taken as controls. The lipid profiles were tested again 6 months after standard cyclosporin A（CsA）treatment in patients with AA. For all the patients, those with a history of hyperlipidemia, diabetes, obesity (body mass index > 28 kg/m 2) or complications with other malignant diseases at diagnosis were excluded. Results: The study enrolled 15 patients with AA, 11 patients with h-MDS and 20 healthy controls. All the enrolled AA patients were non-severe and transfusion dependent, and were treated with CsA 3-5mg/kg/d for at least 6 months. For h-MDS patients, five were MDS with single lineage dysplasia, three were MDS with multilineage dysplasia, and three were MDS-Excess Blasts 1 (MDS-RAEB1). Metabolites in arachidonic acid pathway and retinol metabolism were significantly decreased in the AA patients compared with the healthy controls (P<0.05). AA patients had decreased arachidonic acid pathway metabolites and retinol metabolism-related metabolites as compared with h-MDS（P<0.05), whereas h-MDS patients had increased metabolism of proline and threonine and abnormal sphingolipid metabolism compared with AA patients and the normal controls. After 6-month of CsA treatment, leukotriene B4, 15(S)-HETE, all-trans-retinal and protectin D1 decreased significantly. Patients who had response to CsA had higher levels of baseline protectin D1 (p=0.011), leukotriene B4 (p=0.011), 15(S)-HETE (p=0.004) and all-trans-retinal (p=0.000) than those who had no response. Conclusion: The lipid profiles showed significant difference not only between patients with AA and healthy controls, but also between AA and h-MDS. Meanwhile, some of baseline value and the change in lipid molecules may predict the CsA response at 6 months. Disclosures No relevant conflicts of interest to declare.

A multi-tiered map of EMT defines major transition points and identifies vulnerabilities

TGFβ mediated epithelial to mesenchymal transition (EMT) proceeds through hybrid "E/M" states. A deeper understanding of these states and events which regulate entry to and exit from the E/M states is needed for therapeutic exploitation. We quantified >60,000 molecules across ten time points and twelve omic layers in mammary epithelial cells. Proteomes of whole cells, phosphoproteins, nucleus, extracellular vesicles, secretome and membrane resolved major shifts, E→E/M and E/M→M during EMT, and defined state-specific signatures. Metabolomics identified early activation of arachidonic acid pathway and an enzyme-mediated switch from Cytochrome P450 to Cyclooxygenase / Lipoxygenase branches during E→E/M. Single-cell transcriptomics identified GLIS2 as an early modulator of EMT. Integrative modeling-predicted combinatorial inhibition of AURKB, PP2A and SRC exposed vulnerabilities at E→E/M juncture. Covariance analysis revealed remarkable discordance between proteins and transcripts, and between proteomic layers, implying insufficiency of current approaches. Overall, this dataset provides an unprecedented resource on TGFβ signaling, EMT and cancer.

Intersecting Mechanisms of Hypoxia and Prostaglandin E2-Mediated Inflammation in the Comparative Biology of Oral Squamous Cell Carcinoma

The importance of inflammation in the pathogenesis of cancer was first proposed by Rudolph Virchow over 150 years ago, and our understanding of its significance has grown over decades of biomedical research. The arachidonic acid pathway of inflammation, including cyclooxygenase (COX) enzymes, PGE2 synthase enzymes, prostaglandin E2 (PGE2) and PGE2 receptors has been extensively studied and has been associated with different diseases and different types of cancers, including oral squamous cell carcinoma (OSCC). In addition to inflammation in the tumour microenvironment, low oxygen levels (hypoxia) within tumours have also been shown to contribute to tumour progression. Understandably, most of our OSCC knowledge comes from study of this aggressive cancer in human patients and in experimental rodent models. However, domestic animals develop OSCC spontaneously and this is an important, and difficult to treat, form of cancer in veterinary medicine. The primary goal of this review article is to explore the available evidence regarding interaction between hypoxia and the arachidonic acid pathway of inflammation during malignant behaviour of OSCC. Overlapping mechanisms in hypoxia and inflammation can contribute to tumour growth, angiogenesis, and, importantly, resistance to therapy. The benefits and controversies of anti-inflammatory and anti-angiogenic therapies for human and animal OSCC patients will be discussed, including conventional pharmaceutical agents as well as natural products.

Multi-omic Analysis of Familial Adenomatous Polyposis Reveals Molecular Pathways and Polyclonal Spreading Associated with Early Tumorigenesis

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected patients, leading to colorectal cancer (CRC), and is an ideal model to study early transition to CRC. We performed deep multi-omic profiling of 135 normal mucosal, benign and dysplastic polyps and adenocarcinoma samples from 6 FAP patients who consented to broad data sharing. Whole genome sequencing indicates that spatially separated polyps from the same donor harbor numerous mutations in common, but evolve independently, consistent with a model of polyclonal origin and spreading. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during early hyperplasia, dysplasia and cancer formation. These involve processes such as cell proliferation, immune response, alterations in metabolism (including amino acids, lipids), hormones, and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin/NSAIDs, a common preventative treatment of FAP patients. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in cancer formation and potential mechanisms of pharmaceutical prophylaxis.

A Systematic Review on the Role of Arachidonic Acid Pathway in Multiple Sclerosis

Background & Objective: Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by destruction of oligodendrocytes, immune cell infiltration and demyelination. Inflammation plays a significant role in MS, and the inflammatory mediators such as eicosanoids, leukotrienes, superoxide radicals are involved in pro-inflammatory responses in MS. In this systematic review we tried to define and discuss all the findings of in vivo animal studies and human clinical trials on the potential association between arachidonic acid (AA) pathway and multiple sclerosis. Methods: A systematic literature search across Pubmed, Scopus, Embase and Cochrane database was conducted. This systematic review was performed according to PRISMA guidelines. Results: A total of 146 studies were included, of which 34 were conducted in animals, 58 in humans, and 60 studies reported the role of different compounds that target AA mediators or their corresponding enzymes/ receptors, and can have a therapeutic effect in MS. These results suggest that eicosanoids have significant roles in experimental autoimmune encephalomyelitis (EAE) and MS. The data from animal and human studies elucidated that PGI2, PGF2α, PGD2, isoprostanes, PGE2, PLA2, LTs are increased in MS. PLA2 inhibition modulates the progression of the disease. PGE1 analogues can be a useful option in the treatment of MS. Conclusions: All studies reported the beneficial effects of COX and LOX inhibitors in MS. The hybrid compounds, such as COX-2 inhibitors/TP antagonists and 5-LOX inhibitors can be an innovative approach for multiple sclerosis treatment. Future work in MS should shed light in synthesizing new compounds targeting arachidonic acid pathway.