Angiogenesis Signaling Research Articles

A metabolic role for CD47 in pancreatic β cell insulin secretion and islet transplant outcomes.

Diabetes is a global public health burden and is characterized clinically by relative or absolute insulin deficiency. Therapeutic agents that stimulate insulin secretion and improve insulin sensitivity are in high demand as treatment options. CD47 is a cell surface glycoprotein implicated in multiple cellular functions including recognition of self, angiogenesis, and nitric oxide signaling; however, its role in the regulation of insulin secretion remains unknown. Here, we demonstrate that CD47 receptor signaling inhibits insulin release from human as well as mouse pancreatic β cells and that it can be pharmacologically exploited to boost insulin secretion in both models. CD47 depletion stimulated insulin granule exocytosis via activation of the Rho GTPase Cdc42 in β cells and improved glucose clearance and insulin sensitivity in vivo. CD47 blockade enhanced syngeneic islet transplantation efficiency and expedited the return to euglycemia in streptozotocin-induced diabetic mice. Further, anti-CD47 antibody treatment delayed the onset of diabetes in nonobese diabetic (NOD) mice and protected them from overt diabetes. Our findings identify CD47 as a regulator of insulin secretion, and its manipulation in β cells offers a therapeutic opportunity for diabetes and islet transplantation by correcting insulin deficiency.

Machine Learning Developed a Programmed Cell Death Signature for Predicting Prognosis, Ecosystem, and Drug Sensitivity in Ovarian Cancer.

Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer-related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer. The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single-cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients. The prognostic CDS constructed by the combination of StepCox (n = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C-index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1-like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer-related hallmarks, including angiogenesis, epithelial-mesenchymal transition, hypoxia, glycolysis, and notch signaling. The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.

Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous and lethal. Long noncoding RNAs (lncRNAs) are an important class of genes regulating tumorigenesis and progression. Prior bulk transcriptomic studies in PDAC have revealed the dysregulation of lncRNAs but lack single-cell resolution to distinguish lncRNAs in tumor-intrinsic biology and the tumor microenvironment (TME). We analyzed single-cell transcriptome data from 73 multiregion samples in 21 PDAC patients to evaluate lncRNAs associated with intratumoral heterogeneity and the TME in PDAC. We found 111 cell-specific lncRNAs that reflected tumor, immune and stromal cell contributions, associated with outcomes,and validated across orthogonal datasets. Single-cell analysis of tumor cells revealed lncRNAs associated with TP53 mutations and FOLFIRINOX treatment that were obscured in bulk tumor analysis. Lastly, tumor subcluster analysis revealed widespread intratumor heterogeneity and intratumoral lncRNAs associated with cancer hallmarks and tumor processes such as angiogenesis, epithelial-mesenchymal transition, metabolism and immune signaling. Intratumoral subclusters and lncRNAs were validated across six datasets and showed clinically relevant associations with patient outcomes. Our study provides the first comprehensive assessment of the lncRNA landscape in PDAC using single-cell transcriptomic data and can serve as a resource, PDACLncDB (accessible at https://www.maherlab.com/pdaclncdb-overview), to guide future functional studies.

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

Metastasis, the dissemination of tumor cells, stands as the second most prominent contributor to mortality arising from breast cancer. To counteract this phenomenon, the molecular markers associated with angiogenesis, particularly vascular endothelial growth factor (VEGF) and its receptor (VEGFR), have emerged as promising strategies for impeding the progression of tumor cells. Compounds like pyrimidines, coumarins, oxadiazoles, and triazoles have undergone comprehensive investigations due to their notable anticancer potential, highlighting their encouraging capacities in inhibiting VEGFR-2, an essential mediator of angiogenesis signaling. Herein, we have synthesized pyrimidine–triazoles and oxadiazole–triazoles using electrochemical and conventional methods. The newly synthesized compounds were evaluated for anticancer activity against MCF-7 breast cancer cells, and it was found that the compounds 8a and 8b showed IC50 values of 5.29 and 15.54 μM, respectively. Our in silico mode of action revealed that these compounds could target VEGFR-2, which was further evidenced by our in silico structure-based bioinformatic analysis. In conclusion, we reported an electrochemical method to prepare novel drug-like compounds, based on triazole and other heterocyclic hybrids, that could be used to design VGFR-targeting drugs.

Periostin promotes extensive neovascularization in placenta accreta spectrum disorders via Notch signaling

Objective Extensive neovascularization, closely linked to massive intraoperative blood loss, is a pathological hallmark of placenta accreta spectrum (PAS) cases. This study aims to explore proteins related to neovascularization and elucidate their regulatory roles in PAS, enhancing our understanding of this condition. Methods The isobaric tags for relative and absolute quantitation technique were used to identify and quantify the differentially expressed proteins in placentas from PAS and healthy pregnant women. Immunofluorescence staining and western blot analysis were conducted to determine the protein expression and localization. Gain-of-function experiments were used to conduct cell proliferation and migration assays. In addition, the tube formation assay was performed to evaluate angiogenesis in vitro. The Notch inhibitor DAPT was used to determine the involvement of Notch signaling in angiogenesis in PAS. Results Periostin (POSTN) exhibited higher expression in PAS placentas than in normal placentas. Moreover, the overexpression of POSTN in endothelial cells promoted cell proliferation, mobility, and endothelial angiogenesis via the Notch signaling pathway in vitro. Conclusion Elevated POSTN expression in PAS is associated with increased angiogenesis, indicating its potential as a molecular marker for significant intraoperative blood loss.

Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals.

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first identified human retrovirus responsible for two significant diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although the majority of infected individuals remain asymptomatic carriers, a small percentage may develop ATLL or HAM/TSP. In tumorigenesis, a crucial process is angiogenesis, which involves the formation of new blood vessels. However, the precise mechanism of HTLV-1 associated angiogenesis remains unclear. This study aims to investigate the gene regulation involved in the angiogenesis signaling pathway associated with HTLV-1 infection. The research enrolled 20 male participants, including asymptomatic carriers and healthy individuals. Blood samples were collected and screened using ELISA for HTLV-1 confirmation, and PCR was performed for both Tax and HBZ for validation. RNA extraction and cDNA synthesis were carried out, followed by RT-qPCR analysis targeting cellular genes involved in angiogenesis. Our findings indicate that gene expression related to angiogenesis was elevated in HTLV-1 ACs patients. However, the differences in gene expression of the analyzed genes, including HSP27, Paxillin, PDK1, PTEN, RAF1, SOS1, and VEGFR2 between ACs and healthy individuals were not statistically significant. This suggests that although angiogenesis-related genes may show increased expression in HTLV-1 infection, they might not be robust indicators of ATLL progression in asymptomatic carriers. The results of our study demonstrate that angiogenesis gene expression is altered in ACs of HTLV-1, indicating potential involvement of angiogenesis in the early stages before ATLL development. While we observed elevated angiogenesis gene expression in ACs, the lack of statistical significance between ACs and healthy individuals suggests that these gene markers may not be sufficient on their own to predict the development of ATLL in asymptomatic carriers.

Melatonin modulates the in vitro angiogenesis of granulosa cells collected from women with marital infertility for IVF

Melatonin concentration is
 several folds higher in the follicular fluid than that in blood suggesting an
 important role of this molecule on follicular physiology. However, the actions
 of melatonin on angiogenesis in granulosa cells are currently unknown. In this
 study, we have specifically investigated the potential effects of melatonin on
 the angiogenesis in granulosa cells from female individuals with marital
 infertility. Sixty patients who were submitted to the in vitrofertilization were included. The granulosa-luteal cells of these females were
 collected for cell culture. The cells were divided into four groups: a) vehicle
 (control); b) 0.1 µM melatonin; c) 1 µM melatonin; d) 10 µM melatonin treated
 groups, respectively. After a period of 10 days of culture, expression of genes
 involved in the angiogenesis signaling pathway were analyzed by Real-Time PCR
 and Western Blot assays. The results showed that the expressions of FGF1(fibroblast growth factor 1), IL1B (interleukin 1-beta), VEGFR-2(type 2 vascular-endothelial growth factor receptor), and TGFB1 (tumor
 growth factor 1- beta) were significantly upregulated in melatonin treated
 groups compared to the control. In contrast, the expressions of HIF-1A(hypoxia-inducing factor 1-alpha), FGF2 (fibroblastic growth factor 2), IGF-1(insulin-like growth factor 1), and VEGFA (vascular endothelial growth
 factor alpha) were significantly downregulated by melatonin compared to the
 control. The results suggest that melatonin modulates angiogenesis of granulosa
 cells from women with marital infertility. The underlining mechanism may relate
 to melatonin maintaining the homeostasis of VEGF, especially at a low dose of
 melatonin.

Identification of M2-like macrophage-related signature for predicting the prognosis, ecosystem and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common malignancies worldwide, representing a big health-care challenge globally. M2-like macrophages are significantly correlated with tumor progression, metastasis and treatment resistance. Integrative 10 machine learning algorithms were performed to developed a M2-like macrophage related prognostic signature (MRPS). Single-cell RNA-sequencing analysis was performed to dissect the ecosystem of HCC. Several approaches, including TIDE score, immunophenoscore, TMB score and tumor escape score were used to evaluate the predictive role of MRPS in immunology response. The optimal MRPS constructed by the combination of stepCox + superPC algorithm served as an independent risk factor and showed stable and powerful performances in predicting the overall survival rate of HCC patients with 2-, 3-, and 4-year AUCs of 0. 763, 0.751, and 0.699 in TCGA cohort. HCC patients with low risk score possessed a more interaction of immunoactivated cells, including NK, CD8+ cytotoxic T, and activated B, and a less interaction of immunosuppressive cells, including Treg, CD4+ exhauster T, and M2-like macrophage. Low risk score indicated a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score in HCC, suggesting a better immunotherapy response. The IC50 value of docetaxel, gemcitabine, crizotinib and Osimertinib in HCC with high risk score were lower versus that with low risk score. HCC patients with high risk score had a higher score of cancer-related hallmarks, including angiogenesis, DNA repair, EMT, glycolysis, and NOTCH signaling. Our study proposed a novel MRPS for predicting the prognosis, ecosystem and immunotherapy response in HCC.

Revealing mechanism of Methazolamide for treatment of ankylosing spondylitis based on network pharmacology and GSEA

Methazolamide is a carbonic anhydrase (CA) inhibitor with satisfactory safety. Our previous studies have demonstrated the elevation of CA1 expression and the therapeutic effect of Methazolamide in Ankylosing spondylitis (AS). In this study, we explored the pathogenic role of CA1 and the pharmacological mechanism of Methazolamide in AS through Gene Set Enrichment Analysis (GSEA) and network pharmacology. Seven out of twelve CA1 related gene sets were enriched in AS group. CA1 was core enriched in above seven gene sets involving zinc ion binding, arylesterase activity and one carbon metabolic process. Functional analysis of the candidate target genes obtained from the intersection of AS associated genes and Methazolamide target genes indicated that Methazolamide exerts therapeutic effects on AS mainly through inflammatory pathways which regulate the production of tumor necrosis factor, IL-6 and nitric oxide. PTGS2, ESR1, GSK3β, JAK2, NOS2 and CA1 were selected as therapeutic targets of Methazolamide in AS. Molecular docking and molecular dynamics simulations were performed successfully. In addition, we innovatively obtained the intersection of Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and GSEA results, and found that 18 GO terms and 5 KEGG terms were indicated in the pharmacological mechanism of Methazolamide in AS, involving bone mineralization, angiogenesis, inflammation, and chemokine signaling pathways. Nevertheless, validation for these mechanisms is needed in vivo/vitro experiments.

Distinct molecular targets of ProEGCG from EGCG and superior inhibition of angiogenesis signaling pathways for treatment of endometriosis

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus. Angiogenesis is a major pathophysiology in endometriosis. Our previous studies have demonstrated that the prodrug of epigallocatechin gallate (ProEGCG) exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate (EGCG). However, their direct binding targets and underlying mechanisms for the differential effects remain unknown. In this study, we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis. Additionally, 1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin (MTDH) and PX domain containing serine/threonine kinase-like (PXK) as novel binding targets of EGCG and ProEGCG, respectively. Computational simulation and BioLayer interferometry were used to confirm their binding affinity. Our results showed that MTDH-EGCG inhibited protein kinase B (Akt)-mediated angiogenesis, while PXK-ProEGCG inhibited epidermal growth factor (EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor (HIF-1a)/vascular endothelial growth factor (VEGF) pathway. In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways. Moreover, our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Selenium in Prostate Cancer: Prevention, Progression, and Treatment.

Selenium, a trace mineral with various biological functions, has become a focal point in prostate cancer research. This review aims to present a comprehensive overview of selenium's involvement in prostate cancer, covering its impact on prevention, development, treatment, and underlying mechanisms. Observational studies have revealed a link between selenium levels and selenoproteins with prostate cancer progression. However, randomized controlled studies have shown that selenium supplementation does not prevent prostate cancer (HR: 0.95; 95% CI 0.80-1.13). This discrepancy might be attributed to selenoprotein single nucleotide polymorphisms. In the context of combinatorial therapy, selenium has demonstrated promising synergistic potential in the treatment of prostate cancer. Emerging evidence highlights the significant role of selenium and selenoproteins in prostate cancer, encompassing AR signaling, antioxidative properties, cell death, cell cycle regulation, angiogenesis, epigenetic regulation, immunoregulation, epithelial-mesenchymal transformation, and redox signal. In conclusion, selenium's diverse properties make it a promising trace mineral in prostate cancer prevention, development, and treatment and as a platform for exploring novel agents.

Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis

Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D2 is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D2 metabolite, 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-β antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis.

Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.

Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous influx of metabolic substrates from the blood. Disruption of this process can lead to impairment of neurological functions, loss of consciousness, and coma within minutes. Intricate neurovascular networks permit both spatially and temporally appropriate metabolic substrate delivery. Lactate is the end product of anaerobic or aerobic glycolysis, converted from pyruvate by lactate dehydrogenase-5 (LDH-5). Although abundant in the brain, it was traditionally considered a byproduct or waste of glycolysis. However, recent evidence indicates lactate may be an important energy source as well as a metabolic signaling molecule for the brain and astrocytes-the most abundant glial cell-playing a crucial role in energy delivery, storage, production, and utilization. The astrocyte-neuron lactate-shuttle hypothesis states that lactate, once released into the extracellular space by astrocytes, can be up-taken and metabolized by neurons. This review focuses on this hypothesis, highlighting lactate's emerging role in the brain, with particular emphasis on its role during development, synaptic plasticity, angiogenesis, and disease.

The mechanism of copper homeostasis and its role in disease

AbstractCopper (Cuprum) is an essential trace metal indispensable for the function of numerous enzymatic molecules implicated in cellular metabolism. Emerging evidence has demonstrated the role of copper in angiogenesis and cellular signaling. Moreover, raised copper levels have been detected in hepatocellular carcinoma and other cancers. An inherited or acquired copper imbalance, including inadequately low or excessively high copper levels, as well as inappropriate copper distribution in the body, is implicated in a number of diseases. In addition, a recent groundbreaking study identified a copper‐induced type of programmed cell death named cuprotosis, the mechanism of which greatly deferred from that of other known cell death modes. The first part provides an overview of the regulation of copper homeostasis and discusses the underlying mechanisms of cuprotosis. In the second part, the authors focus on the functions of copper in liver diseases and other metabolic disorders, before discussing how this knowledge could contribute to the development of effective targets to treat such diseases.

Abstract P1102: Organic Semiconductor Photomodulation Enhances Maturation Of Pluripotent Stem Cell-derived Cardiomyocytes

Cardiomyocytes differentiated from pluripotent stem cells (PSC-CMs) hold a great potential for the study and the cure of cardiovascular disease; indeed they have been largely used as platform for disease modeling and drugs testing, and represent a promising source of cells for regenerative therapies. However, their immature phenotype represents a major hurdle for their full application; indeed, PSC-CMs differ from adult ones for molecular, metabolic and morpho-functional properties. Recently, a new technology based on optical excitation of organic semiconductors (OS) has been shown to be able to modulate the behavior of many cell types by targeting different cellular processes, as proliferation, angiogenesis and calcium signalling. Here, we adopted a multidisciplinary approach based on morpho-functional, metabolic and transcriptional analyses to study the effect of OS-photoexcitation on PSC-CMs, by the use of a red-light sensitive OS polymer, namely Poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta [2,1-b;3,4-b']dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT), in the form of a thin film. Our results revealed a significant modulation of markers of maturation in PSC-CMs exposed to PCPDTBT and photomodulation, showing increased size, a shift of their maximal diastolic potential toward more negative values, and augmented Ca 2+ transient amplitude. Moreover, by Scanning ElectroChemical Microscopy (SECM) we found a decrease in glucose uptake and lactate release upon PCPDTBT light stimulation, potentially indicating a switch toward a more adult-like metabolism in stimulated PSC-CMs. Recently obtained RNA sequencing data are in line with these results, and will provide us with hints on the underlying molecular mechanisms. In conclusion, although not definitive, our data are in support of a potential effect of polymer-mediated optical photoexcitation in boosting PSC-CMs toward a more mature phenotype. The demonstration of a relevant effect of OS-photomodulation on PSC-CM maturation and functionality will significantly promote their full applications toward personalized medicine.This research was supported by EU Horizon 2020 FETOPEN- 2018-2020 Programme ‘LION- HEARTED’-GA #828984

Single-cell and bulk transcriptomics reveals M2d macrophages as a potential therapeutic strategy for mucosal healing in ulcerative colitis.

Mucosal healing is essential for treating ulcerative colitis (UC), which results from imbalanced macrophage polarization and dysregulated inflammatory responses. However, the mechanisms of cellular communication and signal transduction that regulate mucosal healing among macrophage subtypes require further investigation. We use bulk and single-cell RNA sequencing analysis to reveal that macrophage subtypes vary in different UC states. At the same time, chemokine and angiogenesis signaling is strongly associated with M2 macrophage's infiltrated proportion. To get more insight into subtypes of macrophages in mucosal healing, we divided macrophages into M1, M2b, and M2d macrophages. Based on the differentially expressed genes (DEGs) between M2d and M1 macrophages, KEGG and GO analysis highlights M2d macrophages' ability to alleviate inflammation and promote epithelial healing. Trajectory analysis revealed opposite differentiation of macrophage subsets between UC and healthy groups, with M1 and M2d macrophages coexisting in the same differentiation branch under UC conditions. Along the pseudotime axis, CCL3 and VEGFA expression increased in UC, while IL10RA remained stable in UC but increased in healthy controls. CellChat identified CCL3-CCR1 has strong communication between M1 and M2d macrophages, while the IL10 signaling pathway is activated explicitly in M2d macrophages to mitigate inflammation and promote epithelial healing. We also speculate that high levels of VEGFA activate endothelial cells expressing VEGFR and worsen inflammation. To conclude, we suggested IL10 and VEGF signaling in M2d macrophages as potential therapeutic targets for mucosal healing. However, it is necessary to establish reliable methods for isolating and purifying M2d macrophages before these targets can be effectively utilized.

Gastrointestinal bleeding and pro-angiogenic shift in the angiopoietin axis with continuous flow left ventricular assist device implantation

BackgroundGastrointestinal bleeding (GIB) affects up to 40% of continuous-flow left ventricular assist device (CF-LVAD) recipients. A higher risk of GIB is seen in CF-LVAD recipients with lower device pulsatility without a known mechanism. One hypothesis is that the novel hemodynamics in CF-LVAD recipients affect angiogenesis signaling. We aimed to (1) measure serum levels of angiopoietin (Ang)-1, Ang-2, and VEGF-A in CF-LVAD recipients with and without GIB and in healthy controls and (2) evaluate correlations of those levels with hemodynamics. MethodsWe recruited 12 patients with CF-LVADs (six who developed GIB after device implantation) along with 12 age-matched controls without heart failure or GIB and measured Ang-1, Ang-2, and VEGF-A levels in serum samples from each patient. ResultsCF-LVAD recipients had significantly higher Ang-2 and lower Ang-1 levels compared to controls with no difference in VEGF-A levels. CF-LVAD recipients with GIB had lower Ang-1 levels than those without GIB. There were trends for pulse pressure to be positively correlated with Ang-1 levels and negatively correlated with Ang-2 levels in CF-LVAD recipients with no correlation observed in healthy controls. ConclusionCF-LVAD recipients demonstrated a shift toward a pro-angiogenic phenotype in the angiopoietin axis that is significantly associated with GIB and may be linked to low pulse pressure.

New insights into the natural history of bronchopulmonary dysplasia from proteomics and multiplexed immunohistochemistry.

Bronchopulmonary dysplasia (BPD) is a disease of prematurity related to the arrest of normal lung development. The objective of this study was to better understand how proteome modulation and cell-type shifts are noted in BPD pathology. Pediatric human donors aged 1-3 yr were classified based on history of prematurity and histopathology consistent with "healed" BPD (hBPD, n = 3) and "established" BPD (eBPD, n = 3) compared with respective full-term born (n = 6) age-matched term controls. Proteins were quantified by tandem mass spectroscopy with selected Western blot validations. Multiplexed immunofluorescence (MxIF) microscopy was performed on lung sections to enumerate cell types. Protein abundances and MxIF cell frequencies were compared among groups using ANOVA. Cell type and ontology enrichment were performed using an in-house tool and/or EnrichR. Proteomics detected 5,746 unique proteins, 186 upregulated and 534 downregulated, in eBPD versus control with fewer proteins differentially abundant in hBPD as compared with age-matched term controls. Cell-type enrichment suggested a loss of alveolar type I, alveolar type II, endothelial/capillary, and lymphatics, and an increase in smooth muscle and fibroblasts consistent with MxIF. Histochemistry and Western analysis also supported predictions of upregulated ferroptosis in eBPD versus control. Finally, several extracellular matrix components mapping to angiogenesis signaling pathways were altered in eBPD. Despite clear parsing by protein abundance, comparative MxIF analysis confirms phenotypic variability in BPD. This work provides the first demonstration of tandem mass spectrometry and multiplexed molecular analysis of human lung tissue for critical elucidation of BPD trajectory-defining factors into early childhood.NEW & NOTEWORTHY We provide new insights into the natural history of bronchopulmonary dysplasia in donor human lungs after the neonatal intensive care unit hospitalization. This study provides new insights into how the proteome and histopathology of BPD changes in early childhood, uncovering novel pathways for future study.

Electroacupuncture relieves portal hypertension by improving vascular angiogenesis and linking gut microbiota in bile duct ligation rats.

The pathological increase in the intrahepatic resistance and decrease peripheral vascular tone in the development of portal hypertension (PHT). PHT has been linked to lower microbial diversity and weakened intestinal barrier, and interplay alters inflammatory signaling cascades. Electroacupuncture (EA) may ameliorate the inflammatory response and limit arterial vasodilatation and portal pressure. This study addresses the possible mechanisms underlying putative hemodynamics effects of EA in PHT rats. PHT was induced by bile duct ligation (BDL) over 7 days in rats. BDL rats were treated with low-frequency EA (2 Hz) at acupoint, ST36, 10 min once daily for 7 consecutive days. EA significantly reduced portal pressure and enhanced maximum contractile responses in the aorta, and blunts the angiogenesis cascade in PHT rats. EA decreased the aortic angiogenesis signaling cascade, reflected by downregulated of ICAM1, VCAM1, VEGFR1, and TGFβR2 levels. In addition, EA preserved claudin-1, occludin, and ZO-1 levels in BDL-induced PHT model. Furthermore, EA demonstrates to have a positive effect on the gut Bacteroidetes/Firmicutes ratio and to reduce pro-inflammatory cytokines and endotoxins. These results summarize the potential role of EA in the gut microbiota could potentially lead to attenuate intestine injury which could further contribute to vascular reactivity in PHT rats.

Role of miRNAs in Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by autoimmunity, synovial inflammation and joint destruction. Pannus formation in the synovial cavity can cause irreversible damage to the joint and cartilage and eventually permanent disability. Current conventional treatments for RA have limitations regarding efficacy, safety and cost. microRNA (miRNA) is a type of non-coding RNA (ncRNA) that regulates gene expression at the post-transcriptional level. The dysregulation of miRNA has been observed in RA patients and implicated in the pathogenesis of RA. miRNAs have emerged as potential biomarkers or therapeutic agents. In this review, we explore the role of miRNAs in various aspects of RA pathophysiology, including immune cell imbalance, the proliferation and invasion of fibroblast-like synovial (FLS) cell, the dysregulation of inflammatory signaling and disturbance in angiogenesis. We delve into the regulatory effects of miRNAs on Treg/Th17 and M1/M2 polarization, the activation of the NF-κB/NLRP3 signaling pathway, neovascular formation, energy metabolism induced by FLS-cell-induced energy metabolism, apoptosis, osteogenesis and mobility. These findings shed light on the potential applications of miRNAs as diagnostic or therapeutic biomarkers for RA management. Furthermore, there are some strategies to regulate miRNA expression levels by utilizing miRNA mimics or exosomes and to hinder miRNA activity via competitive endogenous RNA (ceRNA) network-based antagonists. We conclude that miRNAs offer a promising avenue for RA therapy with unlimited potential.