Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia.

Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes.

Revealing the molecular landscape of human placenta: a systematic review and meta-analysis of single-cell RNA sequencing studies.

BACKGROUND: With increasing significance of developmental programming effects associated with placental dysfunction, more investigations are devoted to improving the characterization and understanding of placental signatures in health and disease. The placenta is a transitory but dynamic organ adapting to the shifting demands of fetal development and available resources of the maternal supply throughout pregnancy. Trophoblasts (cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts) are placental-specific cell types responsible for the main placental exchanges and adaptations. Transcriptomic studies with single-cell resolution have led to advances in understanding the placenta's role in health and disease. These studies, however, often show discrepancies in characterization of the different placental cell types. OBJECTIVE AND RATIONALE: We aim to review the knowledge regarding placental structure and function gained from the use of single-cell RNA sequencing (scRNAseq), followed by comparing cell-type-specific genes, highlighting their similarities and differences. Moreover, we intend to identify consensus marker genes for the various trophoblast cell types across studies. Finally, we will discuss the contributions and potential applications of scRNAseq in studying pregnancy-related diseases. SEARCH METHODS: We conducted a comprehensive systematic literature review to identify different cell types and their functions at the human maternal-fetal interface, focusing on all original scRNAseq studies on placentas published before March 2023 and published reviews (total of 28 studies identified) using PubMed search. Our approach involved curating cell types and subtypes that had previously been defined using scRNAseq and comparing the genes used as markers or identified as potential new markers. Next, we reanalyzed expression matrices from the six available scRNAseq raw datasets with cell annotations (four from first trimester and two at term), using Wilcoxon rank-sum tests to compare gene expression among studies and annotate trophoblast cell markers in both first trimester and term placentas. Furthermore, we integrated scRNAseq raw data available from 18 healthy first trimester and nine term placentas, and performed clustering and differential gene expression analysis. We further compared markers obtained with the analysis of annotated and raw datasets with the literature to obtain a common signature gene list for major placental cell types. OUTCOMES: Variations in the sampling site, gestational age, fetal sex, and subsequent sequencing and analysis methods were observed between the studies. Although their proportions varied, the three trophoblast types were consistently identified across all scRNAseq studies, unlike other non-trophoblast cell types. Notably, no marker genes were shared by all studies for any of the investigated cell types. Moreover, most of the newly defined markers in one study were not observed in other studies. These discrepancies were confirmed by our analysis on trophoblast cell types, where hundreds of potential marker genes were identified in each study but with little overlap across studies. From 35 461 and 23 378 cells of high quality in the first trimester and term placentas, respectively, we obtained major placental cell types, including perivascular cells that previously had not been identified in the first trimester. Importantly, our meta-analysis provides marker genes for major placental cell types based on our extensive curation. WIDER IMPLICATIONS: This review and meta-analysis emphasizes the need for establishing a consensus for annotating placental cell types from scRNAseq data. The marker genes identified here can be deployed for defining human placental cell types, thereby facilitating and improving the reproducibility of trophoblast cell annotation.

Salmonella-mediated methionine deprivation drives immune activation and enhances immune checkpoint blockade therapy in melanoma.

BACKGROUND: Although immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it is crucial to identify effective drug combinations and develop new therapies for the treatment of melanoma. SGN1, a genetically modified Salmonella typhimurium species that causes the targeted deprivation of methionine in tumor tissues, is currently under investigation in clinical trials. However, the inhibitory effect of SGN1 on melanoma and the benefits of SGN1 in combination with ICIs remain largely unexplored. Therefore, this study aims to investigate the antitumor potential of SGN1, and its ability to enhance the efficacy of antibody-based programmed cell death-ligand 1 (PD-L1) inhibitors in the treatment of murine melanoma. METHODS: The antitumor activity of SGN1 and the effect of SGN1 on the efficacy of PD-L1 inhibitors was studied through murine melanoma models. Further, The Cancer Genome Atlas-melanoma cohort was clustered using ConsensusClusterPlus based on the methionine deprivation-related genes, and immune characterization was performed using xCell, Microenvironment Cell Populations-counter, Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data, and immunophenoscore (IPS) analyses. The messenger RNA data on programmed death-1 (PD-1) immunotherapy response were obtained from the Gene Expression Omnibus database. Gene Set Enrichment Analysis of methionine deprivation-up gene set was performed to determine the differences between pretreatment responders and non-responders. RESULTS: This study showed that both, the intratumoral and the intravenous administration of SGN1 in subcutaneous B16-F10 melanomas, suppress tumor growth, which was associated with an activated CD8+T-cell response in the tumor microenvironment. Combination therapy of SGN1 with systemic anti-PD-L1 therapy resulted in better antitumor activity than the individual monotherapies, respectively, and the high therapeutic efficacy of the combination was associated with an increase in the systemic level of tumor-specific CD8+ T cells. Two clusters consisting of methionine deprivation-related genes were identified. Patients in cluster 2 had higher expression of methionine_deprivation_up genes, better clinical outcomes, and higher immune infiltration levels compared with patients in cluster 1. Western blot, IPS analysis, and immunotherapy cohort study revealed that methionine deficiency may show a better response to ICI therapy CONCLUSIONS：: This study reports Salmonella-based SGN1 as a potent anticancer agent against melanoma, and lays the groundwork for the potential synergistic effect of ICIs and SGN1 brought about by improving the immune microenvironment in melanomas.

Outcomes of SARS-CoV-2 infection in early pregnancy-A systematic review and meta-analysis.

INTRODUCTION: Available data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pregnancy outcomes mostly refer to women contracting the infection during advanced pregnancy or close to delivery. There is limited information on the association between SARS-CoV-2 infection in early pregnancy and outcomes thereof. MATERIAL AND METHODS: We aimed to systematically review the maternal, fetal and neonatal outcomes following SARS-CoV-2 infection in early pregnancy, defined as <20 weeks of gestation (PROSPERO Registration 2020 CRD42020177673). Searches were carried out in PubMed, Medline, EMBASE, and Scopus databases from January 2020 until April 2023 and the WHO database of publications on coronavirus disease 2019 (COVID-19) from December 2019 to April 2023. Cohort and case-control studies on COVID-19 occurring in early pregnancy that reported data on maternal, fetal, and neonatal outcomes were included. Case reports and studies reporting only exposure to SARS-CoV-2 or not stratifying outcomes based on gestational age were excluded. Data were extracted in duplicate. Meta-analyses were conducted when appropriate, using R meta (R version 4.0.5). RESULTS: A total of 18 studies, 12 retrospective and six prospective, were included in this review, reporting on 10 147 SARS-CoV-2-positive women infected in early pregnancy, 9533 neonates, and 180 882 SARS-CoV-2 negative women. The studies had low to moderate risk of bias according to the Newcastle-Ottawa quality assessment Scale. The studies showed significant clinical and methodological heterogeneity. A meta-analysis could be performed only on the outcome miscarriage rate, with a pooled random effect odds ratio of 1.44 (95% confidence interval 0.96-2.18), showing no statistical difference in miscarriage in SARS-CoV-2-infected women. Individual studies reported increased incidences of stillbirth, low birthweight and preterm birth among neonates born to mothers affected by COVID-19 in early pregnancy; however, these results were not consistent among all studies. CONCLUSIONS: In this comprehensive systematic review of available evidence, we identified no statistically significant adverse association between SARS-CoV-2 infection in early pregnancy (before 20 weeks of gestation) and fetal, neonatal, or maternal outcomes. However, a 44% increase in miscarriage rate is concerning and further studies of larger sample size are needed to confirm or refute our findings.

FKBP38 suppresses endometrial cancer cell proliferation and metastasis by inhibiting the mTOR pathway.

Endometrial cancer (EC) is a common gynecological malignancy, and advanced-stage or recurrent EC is associated with a high mortality rate owing to the ineffectiveness of currently available treatments. FK506-binding protein 38 (FKBP38) is a member of the immunophilin family and inhibits melanoma and breast cancer cell metastasis. However, the functions of FKBP38 and its potential mechanism in EC remain unclear. Herein, we analyzed the expression levels of FKBP38 in EC cells and found that the FKBP38 expression was high in Ishikawa cells, and low in AN3CA cells, traditionally considered a low grade and a high grade cell line, respectively, in pathology classification. Moreover, FKBP38 inhibited cell proliferation, migration and invasion in EC cells, FKBP38 knockdown significantly promoted tumor growth of Ishikawa cells in a subcutaneous xenograft model and increased the number of lung metastases of Hec-1-A cells in a metastatic mouse model. Furthermore, FKBP38 suppressed several target proteins of epithelial-to-mesenchymal transition (EMT) and reduced the phosphorylation of ribosomal S6 protein (S6), eukaryotic initiation factor 4E-binding protein 1 (4EBP-1), indicating the potent inhibition of the mammalian target of rapamycin (mTOR) pathway. Meanwhile, the inhibition of mTOR neutralized the elevation of EC cell proliferation, migration and invasion after FKBP38 knockdown. In summary, FKBP38 would exert a tumor-suppressing role by modulating the mTOR pathway. Our results indicate that FKBP38 may be considered as a factor of EC metastasis and a new target for EC therapeutic intervention.

ω-3 polyunsaturated fatty acid alleviates systemic lupus erythematosus by suppressing autoimmunity in a murine model.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease that damages multiple organs by the production of autoantibodies. Numerous research studies have demonstrated the anti-inflammatory effects of ω-3 polyunsaturated fatty acids (PUFAs). A diet rich in ω-3 PUFAs reduces chronic inflammatory and autoimmune conditions. Herein, we investigated the protective effect of ω-3 PUFAs against autoimmune injury in SLE. In a TMPD-induced mouse model of SLE, supplementation with eicosapentaenoic acid (EPA)-rich (97%) fish oil was found to alleviate systemic autoimmune phenotypes such as ascites, lipogranulomas and serum dsDNA levels. In addition, EPA also significantly improved renal manifestations, reducing proteinuria, glomerulonephritis, and immune complex deposition. Mechanistically, ω-3 PUFAs were shown to modulate the differentiation of B lymphocyte subsets of primary splenic lymphocytes in the spontaneous murine lupus model MRL/MpJ-Faslpr in vitro, specifically that both EPA and DHA suppressed the number of total B cells, B1B2 cells and plasma cells. Concurrently, they were also found to promote the secretion of the anti-inflammatory cytokine IL10, mainly produced by Breg and Treg cells. Thus, nutritional supplementation with ω-3 PUFAs can regulate B cell's differentiation and anti-inflammatory function and strongly prevent autoimmune responses and lupus nephritis. The diets balance between ω-6 and ω-3 PUFAs intake may represent a promising treatment strategy to prevent or delay the onset of SLE.

Prognosis prediction based on methionine metabolism genes signature in gliomas.

BACKGROUND: Glioma cells have increased intake and metabolism of methionine, which can be monitored with 11 C-L-methionine. However, a short half-life of 11 C (~ 20 min) limits its application in clinical practice. It is necessary to develop a methionine metabolism genes-based prediction model for a more convenient prediction of glioma survival. METHODS: We evaluated the patterns of 29 methionine metabolism genes in glioma from the Cancer Genome Atlas (TCGA). A risk model was established using Lasso regression analysis and Cox regression. The reliability of the prognostic model was validated in derivation and validation cohorts (Chinese Glioma Genome Atlas; CGGA). GO, KEGG, GSEA and ESTIMATE analyses were performed for biological functions and immune characterization. RESULTS: Our results showed that a majority of the methionine metabolism genes (25 genes) were involved in the overall survival of glioma (logrank p and Cox p < 0.05). A 7-methionine metabolism prognostic signature was significantly related to a poor clinical prognosis and overall survival of glioma patients (C-index = 0.83). Functional analysis revealed that the risk model was correlated with immune responses and with epithelial-mesenchymal transition. Furthermore, the nomogram integrating the signature of methionine metabolism genes manifested a strong prognostic ability in the training and validation groups. CONCLUSIONS: The current model had the potential to improve the understanding of methionine metabolism in gliomas and contributed to the development of precise treatment for glioma patients, showing a promising application in clinical practice.

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study.

Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

Systematic gene therapy derived from an investigative study of AAV2/8 vector gene therapy for Fabry disease.

BACKGROUND: Fabry disease (FD) is a progressive multisystemic disease characterized by a lysosomal enzyme deficiency. A lack of α-galactosidase A (α-Gal A) activity results in the progressive systemic accumulation of its substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which results in renal, cardiac, and/or cerebrovascular disease and early death. Enzyme replacement therapy (ERT) is the current standard of care for FD; however, it has important limitations, including a low half-life, limited distribution, and requirement of lifelong biweekly infusions of recombinant enzymes. METHODS: Herein, we evaluated a gene therapy approach using an episomal adeno-associated viral 2/8 (AAV2/8) vector that encodes the human GLA cDNA driven by a liver-specific expression cassette in a mouse model of FD that lacks α-Gal A activity and progressively accumulates Gb3 and Lyso-Gb3 in plasma and tissues. RESULTS: A pharmacology and toxicology study showed that administration of AAV2/8-hGLA vectors (AAV2/8-hGLA) in FD mice without immunosuppression resulted in significantly increased plasma and tissue α-Gal A activity and substantially normalized Gb3 and Lyso-Gb3 content. CONCLUSIONS: Moreover, the plasma enzymatic activity of α-Gal A continued to be stably expressed for up to 38 weeks and sometimes even longer, indicating that AAV2/8-hGLA is effective in treating FD mice, and that α-Gal A is continuously and highly expressed in the liver, secreted into plasma, and absorbed by various tissues. These findings provide a basis for the clinical development of AAV2/8-hGLA.

Eicosapentaenoic acid metabolites promotes the trans-differentiation of pancreatic α cells to ß cells.

Type 1 diabetes mellitus (T1DM) is characterized by life-threatening absolute insulin deficiency. Although ω-3 polyunsaturated fatty acids (PUFAs) displayed significant anti-hyperglycemic activity, the insulinotropic effects of their metabolites remain unknown. In this study, we took advantage of a transgenic model, mfat-1, that overexpresses an ω-3 desaturase and can convert ω-6 PUFAs to ω-3 PUFAs. Eicosapentaenoic acid (EPA) was sharply elevated in the pancreatic tissues of mfat-1 transgenic mice compared with wild-type (WT) mice. In contrast to the WT mice, the mfat-1 transgenics did not develop overt diabetes and still maintained normal blood glucose levels and insulin secretion following streptozotocin-treatment. Furthermore, under the condition of pancreatic ß-cell damage, co-incubation of the metabolites of EPA produced from the CYP 450 pathway with isolated islets promoted the overexpression of insulin as well as ß-cell specific markers, pdx1 and Nkx6.1 in pancreatic α-cells. Addition of EPA metabolites to the cultured glucagon-positive α-cell lines, a series of pancreatic ß-cell markers were also found significantly elevated. Combined together, these results demonstrated the effects of ω-3 PUFAs and their metabolites on the trans-differentiation from α-cells to ß-cells and its potential usage in the intervention of T1DM.

Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models.

The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.

[Effect of a novel phosphodiesterase 5 inhibitor, CPD1, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury].

This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor ß1 (TGF-ß1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-ß signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.

Endogenous production of ω-3 polyunsaturated fatty acids mitigates cisplatin-induced myelosuppression by regulating NRF2-MDM2-p53 signaling pathway.

Cisplatin is a chemotherapy medication used to treat a wide range of cancers. A common side effect of cisplatin is myelosuppression. Research suggests that oxidative damages are strongly and consistently related to myelosuppression during cisplatin treatment. ω-3 polyunsaturated fatty acids (PUFAs) can enhance the antioxidant capacity of cells. Herein, we investigated the protective benefit of endogenous ω-3 PUFAs on cisplatin-induced myelosuppression and the underlying signaling pathways using a transgenic mfat-1 mouse model. The expression of mfat-1 gene can increase endogenous levels of ω-3 PUFAs by enzymatically converting ω-6 PUFAs. Cisplatin treatment reduced peripheral blood cells and bone marrow nucleated cells, induced DNA damage, increased the production of reactive oxygen species, and activated p53-mediated apoptosis in bone marrow (BM) cells of wild-type mice. In the transgenics, the elevated tissue ω-3 PUFAs rendered a robust preventative effect on these cisplatin-induced damages. Importantly, we identified that the activation of NRF2 by ω-3 PUFAs could trigger an antioxidant response and inhibit p53-mediated apoptosis by increasing the expression of MDM2 in BM cells. Thus, endogenous ω-3 PUFAs enrichment can strongly prevent cisplatin-induced myelosuppression by inhibiting oxidative damage and regulating the NRF2-MDM2-p53 signaling pathway. Elevation of tissue ω-3 PUFAs may represent a promising treatment strategy to prevent the side effects of cisplatin.

Pharmacological targeting of type phosphodiesterase 4 inhibits the development of acute myeloid leukemia by impairing mitochondrial function through the Wnt/ß-catenin pathway.

Acute myeloid leukemia (AML) is prone to drug-resistant relapse with a low 5-year survival rate. New therapeutic modalities are sorely needed to provide hope for AML relapse patients. Herein, we demonstrated a specific inhibitor of type 4 phosphodiesterase (PDE4), Zl-n-91, could significantly reduce the proliferation of AML cells, block DNA replication process, and increase AML cell death. Zl-n-91 also impeded the growth of subcutaneous xenograft and prolonged the survival of the MLL-AF9-driven AML model. Bioinformatic analysis revealed that elevated mitochondrial gene signatures inversely correlate with the survival of AML patients; and importantly, Zl-n-91 strongly suppressed the function of mitochondria. In addition, this PDE4 inhibitor induced alterations in multiple signaling pathways, including the reduction of ß-catenin activity. Stimulation of the Wnt/ß-catenin pathway could attenuate the inhibitory effect of Zl-n-91 on AML cell proliferation as well as mitochondrial function. Taken together, we revealed for the first time that targeting PDE4 activity could attenuate mitochondrial function through a Wnt/ß-catenin pathway, which in turn would block the growth of AML cells. Specific PDE4 inhibitors can potentially serve as a new treatment modality for AML patients.

The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia.

BACKGROUND: Patients with familial hypercholesterolemia (FH) display high levels of low-density lipoprotein cholesterol (LDL-c), endothelial dysfunction, and increased risk of premature atherosclerosis. We have previously shown that red blood cells (RBCs) from patients with type 2 diabetes induce endothelial dysfunction through increased arginase 1 and reactive oxygen species (ROS). OBJECTIVE: To test the hypothesis that RBCs from patients with FH (FH-RBCs) and elevated LDL-c induce endothelial dysfunction. METHODS AND RESULTS: FH-RBCs and LDL-c >5.0 mM induced endothelial dysfunction following 18-h incubation with isolated aortic rings from healthy rats compared to FH-RBCs and LDL-c <2.5 mM or RBCs from healthy subjects (H-RBCs). Inhibition of vascular but not RBC arginase attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. Furthermore, arginase 1 but not arginase 2 was elevated in the vasculature of aortic segments after incubation with FH-RBCs and LDL-c >5.0 mM. A superoxide scavenger, present throughout the 18-h incubation, attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. ROS production was elevated in these RBCs in comparison with H-RBCs. Scavenging of vascular ROS through various antioxidants also attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. This was corroborated by an increase in the lipid peroxidation product 4-hydroxynonenal. Lipidomic analysis of RBC lysates did not reveal any significant changes across the groups. CONCLUSION: FH-RBCs induce endothelial dysfunction dependent on LDL-c levels via arginase 1 and ROS-dependent mechanisms.

Resistin Promotes Nasopharyngeal Carcinoma Metastasis through TLR4-Mediated Activation of p38 MAPK/NF-κB Signaling Pathway.

NPC is a type of malignant tumor with a high risk of local invasion and early distant metastasis. Resistin is an inflammatory cytokine that is predominantly produced from the immunocytes in humans. Accumulating evidence has suggested a clinical association of circulating resistin with the risk of tumorigenesis and a relationship between blood resistin levels and the risk of cancer metastasis. In this study, we explored the blood levels and the role of resistin in NPC. High resistin levels in NPC patients were positively associated with lymph node metastasis, and resistin promoted the migration and invasion of NPC cells in vitro. These findings were also replicated in a mouse model of NPC tumor metastasis. We identified TLR4 as a functional receptor in mediating the pro-migratory effects of resistin in NPC cells. Furthermore, p38 MAPK and NF-κB were intracellular effectors that mediated resistin-induced EMT. Taken together, our results suggest that resistin promotes NPC metastasis by activating the TLR4/p38 MAPK/NF-κB signaling pathways.

Protective effects of isofraxidin against scopolamine-induced cognitive and memory impairments in mice involve modulation of the BDNF-CREB-ERK signaling pathway.

BACKGROUND: Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. OBJECTIVE: This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. MATERIALS & METHODS: Animals were randomly divided into 6 groups, control, vehicle, donepezil (10 mg/kg, p.o.), and isofraxidin (3, 10, and 30 mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1 mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. RESULTS: Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). DISCUSSION & CONCLUSIONS: These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways.

ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. A new approach to treating TNBC is required to improve patient survival. Phosphodiesterase-4 (PDE4) is an enzyme that is predominantly involved in the modulation of intracellular signaling mediated by cAMP. Although the efficacy of PDE4 inhibitors in several human inflammatory diseases is well documented, their clinical utility has been limited by side effects, including nausea and emesis. Recently, PDE4 has been used as a potential therapeutic target for different cancer types. In the present study, we investigated the anticancer effects of a novel PDE4 inhibitor ZL-n-91 on TNBC and the underlying mechanism. We showed that ZL-n-91 inhibited the proliferation of TNBC cells, induced cell apoptosis, and caused cell cycle arrest. Western blot analysis showed that ZL-n-91 increased Bax level and reduced Bcl-2 expression. Furthermore, downregulation of the cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, PCNA, p-RB, and ZL-n-91, significantly inhibited the transcription of DNA repair genes and triggered an intracellular DNA damage response. Moreover, ZL-n-91 prevented the growth of the transplanted MDA-MB-231 tumor xenograft in nude mice and increased the γ-H2AX expression. These data demonstrate the anticancer effects of ZL-n-91 on TNBC cells and suggest its potential use in anticancer therapy.

[Peritoneal dialysis-associated peritonitis caused by Rhizobium species - a case report]. / Rhizobium species visade sig vara orsak till peritonealdialysperitonit.

Peritonitis is a serious complication associated with high morbidity and mortality in patients with peritoneal dialysis (PD). We present a case of PD-associated peritonitis caused by the unusual pathogen Rhizobium. After therapy failure and bacterial growth despite treatment with vancomycin and tobramycin, the treatment was changed to meropenem intravenously and ciprofloxacin intraperitoneally according to antimicrobial susceptibility testing. The patient subsequently recovered without having the PD-catheter removed. To conclude, patients with PD are one of many patient groups at a greater risk of infections with unusual microbial agents, and pathogens that normally do not cause disease should be considered as potential causes of pathology when antibiotic treatment failure occurs.