Evaluation of Renal Microhemodynamics Heterogeneity in Different Strains and Sexes of Mice.

Addressing the existing gaps in our understanding of sex- and strain-dependent disparities in renal microhemodynamics, this study conducts an investigation into the variations in renal function and related biological oscillators. Utilizing the genetically diverse mouse models BALB/c, C57BL/6, and KM, which serve as established proxies for the study of renal pathophysiology, we implemented laser Doppler flowmetry conjoined with wavelet transform analyses to interrogate the dynamic renal microcirculation. Creatinine, urea, uric acid, glucose, and cystatin C, were quantified to investigate potential divergences attributable to sex and genetic lineage. Our findings reveal marked sexual dimorphism in metabolite concentrations, as well as strain-specific variances, particularly in creatinine and cystatin C levels. Through the combination of Mantel tests and Pearson's correlation coefficients, we delineated the associations between renal functional metrics and microhemodynamics, uncovering interactions in female BALB/c mice for creatinine and uric acid, and in male C57BL/6 mice for cystatin C. Histopathological examination confirmed an augmented microvascular density in females and elucidating variations in the expression of estrogen receptor ß amongst the strains. These data collectively highlight the influence of both sex and genetic constitution on renal microcirculation, providing an understanding that may inform the etiological exploration of renal ailments.

Tiny clue reveals the general trend: a bibliometric and visualized analysis of renal microcirculation.

BACKGROUND: Renal microcirculation plays a pivotal role in kidney function by maintaining structural and functional integrity, facilitating oxygen and nutrient delivery, and waste removal. However, a thorough bibliometric analysis in this area remains lacking. Therefore, we aim to provide valuable insights through a bibliometric analysis of renal microcirculation literature using the Web of Science database. METHODS: We collected renal microcirculation-related publications from the Web of Science database from January 01, 1990, to December 31, 2022. The co-authorship of authors, organizations, and countries/regions was analyzed with VOSviewer1.6.18. The co-occurrence of keywords and co-cited references were analyzed using CiteSpace6.1.R6 software to generate visualization maps. Additionally, burst detection was applied to keywords and cited references to forecast research hotspots and future trends. RESULTS: Our search yielded 7462 publications, with the American Journal of Physiology-Renal Physiology contributing the most articles. The United States, Mayo Clinic, and Lerman Lilach O emerged with the highest publication count, indicating their active collaborations. 'Type 2 diabetes' was the most significant keyword cluster, and 'diabetic kidney disease' was the largest cluster of cited references. 'Cardiovascular outcome' and 'diabetic kidney diseases' were identified as keywords in their burst period over the past three years. CONCLUSION: Our bibliometric analysis illuminates the contours of nephrology and microcirculation research, revealing a landscape ripe for challenges and the seeds of future scientific innovation. While the trends discerned from the literature emerging opportunities in diagnostic innovation, renal microcirculation research, and precision medicine interventions, their translation to clinical practice is anticipated to be a deliberate process.

Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials.

Background: Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review and meta-analysis evaluated the effectiveness of ranolazine, an antianginal agent, in improving coronary microvascular function. Methods: We conducted a comprehensive literature search of the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, the Chinese BioMedical Literature Database, and gray literature databases until September 30, 2023. The included studies were randomized controlled trials (RCTs) published in the English or Chinese languages that screened for eligibility using two independent investigators. Risk of bias was evaluated with the Cochrane Collaboration tool. Subgroup and sensitivity analyses were used to identify sources of heterogeneity. Meta-analysis was performed using RevMan version 5.4 (Cochrane) and Stata version 16.0 (StataCorp). Results: From 1,470 citations, 8 RCTs involving 379 participants were included in this analysis. Our findings showed that ranolazine increased coronary flow reserve (CFR) over an 8 to 12-week follow-up period [standardized mean difference =1.16; 95% confidence interval (CI): 0.4-1.89; P=0.002]. Ranolazine increased the global myocardial perfusion reserve index (MPRI) [weighted mean difference (WMD) =0.18; 95% CI: 0.07-0.29; P=0.002] and the midsubendocardial MPRI (WMD =0.10; 95% CI: 0.02-0.19; P=0.02). Moreover, ranolazine improved 3 of the 5 Seattle Angina Questionnaire scores, namely, physical functioning (WMD =4.89; 95% CI: 0.14 to 9.64; P=0.04), angina stability (WMD =17.31; 95% CI: 7.13-27.49; P=0.0009), and quality of life (WMD =10.11; 95% CI: 3.57-16.65; P=0.0003). Trial sequential analysis showed that the meta-analysis of angina stability and quality of life scores had a sufficient sample size and statistical power. Conclusions: Our analysis suggests that ranolazine is associated with improvements in CFR, myocardial perfusion, and the Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease. However, further large-scale RCTs with long-term follow-up are recommended to validate these findings and provide a more comprehensive understanding of the effects of ranolazine on coronary microvascular function.

Characteristics of Inflammatory and Normal Endothelial Exosomes on Endothelial Function and the Development of Hypertension.

Endothelial dysfunction is associated with the development of hypertension. We hypothesize that inflammatory and normal endothelial exosomes play their roles by mediating endothelial function, and they induce endothelial angiogenesis through different signaling pathways. Endothelial cell-derived exosomes were isolated from the human umbilical vein endothelial cells (HUVECs) treated with (TExo) or without (CExo) tumor necrosis factor (TNF)-α. We monitored dermal microcirculation profiles in spontaneously hypertensive rats (SHRs) and WKY rats using a laser Doppler imager and a laser Doppler perfusion and temperature monitor. Tube formation, levels of angiogenesis-related proteins in HUVEC-conditioned media, and reactive oxygen species (ROS) levels were assessed following TNF-α, CExo, or TExo treatments. Western blot analysis was conducted to examine signaling proteins associated with inflammation and ROS. The results showed increased blood perfusion and the mean amplitude of endothelial oscillator in SHRs following CExo administration. TNF-α, CExo, and TExo treatments promoted endothelial tube formation and elevated levels of angiogenic factors and ROS. TExo significantly increased phosphorylation levels of STAT3, p38, and level of NF-κB, while decreasing phosphorylation levels of JNK and Erk (P < 0.01 or P < 0.05). CExo significantly increased STAT3 phosphorylation and reduced JNK and Erk phosphorylation (all P < 0.01). In conclusion, TNF-α and TExo induce inflammatory and pathological angiogenesis via the NF-κB pathway, while CExo exhibits a physiologically pro-angiogenic effect on endothelial cells. Increased ROS, interplaying with inflammatory signals, contribute to exosome-mediated alterations of endothelial function, thereby playing a role in the development of hypertension.

Research progress of absorbable stents.

Atherosclerosis, a chronic inflammation of blood vessel walls, is a progressive pathophysiological process characterized by lipid deposition and innate adaptive immune responses. Arteriosclerosis often leads to narrowing of blood vessels. At present, interventional stent therapy is the main treatment method for vascular stenosis, which has the advantages of less trauma, less risk and faster recovery. However, atherosclerosis occurs in a complex pathophysiological environment. Stenting inevitably causes local tissue damage, leading to complications such as inflammation, intimal hyperplasia, late thrombosis, stent restenosis and other complications. It is urgent to optimize interventional therapy program. This article summarizes the advantages and disadvantages of absorbable metal scaffolds and the research progress of absorbable polymer scaffolds. The optimization strategy of stent is proposed. The status quo of drug coating was summarized. The prospect of new stent. To improve the therapeutic effect of arteriosclerosis.

Harnessing the benefits of glycine supplementation for improved pancreatic microcirculation in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is predominantly managed using insulin replacement therapy, however, pancreatic microcirculatory disturbances play a critical role in T1DM pathogenesis, necessitating alternative therapies. This study aimed to investigate the protective effects of glycine supplementation on pancreatic microcirculation in T1DM. Streptozotocin-induced T1DM and glycine-supplemented mice (n = 6 per group) were used alongside control mice. Pancreatic microcirculatory profiles were determined using a laser Doppler blood perfusion monitoring system and wavelet transform spectral analysis. The T1DM group exhibited disorganized pancreatic microcirculatory oscillation. Glycine supplementation significantly restored regular biorhythmic contraction and relaxation, improving blood distribution patterns. Further-more, glycine reversed the lower amplitudes of endothelial oscillators in T1DM mice. Ultrastructural deterioration of islet microvascular endothelial cells (IMECs) and islet microvascular pericytes, including membrane and organelle damage, collagenous fiber proliferation, and reduced edema, was substantially reversed by glycine supplementation. Additionally, glycine supplementation inhibited the production of IL-6, TNF-α, IFN-γ, pro-MMP-9, and VEGF-A in T1DM, with no significant changes in energetic metabolism observed in glycine-supplemented IMECs. A statistically significant decrease in MDA levels accompanied by an increase in SOD levels was also observed with glycine supplementation. Notably, negative correlations emerged between inflammatory cytokines and microhemodynamic profiles. These findings suggest that glycine supplementation may offer a promising therapeutic approach for protecting against pancreatic microcirculatory dysfunction in T1DM.

Reordering and synchronization of electrical turbulence in cardiac tissue through global and partial optogenetical illumination.

Electrical turbulence in the heart is considered the culprit of cardiac disease, including the fatal ventricular fibrillation. Optogenetics is an emerging technology that has the capability to produce action potentials of cardiomyocytes to affect the electric wave propagation in cardiac tissue, thereby possessing the potential to control the turbulence, by shining a rotating spiral pattern onto the tissue. In this paper, we present a method to reorder and synchronize electrical turbulence through optogenetics. A generic two-variable reaction-diffusion model and a simplified three-variable ionic cardiac model are used. We discuss cases involving either global or partial illumination.

Global trend and future landscape of coronary microcirculation: A bibliometric and visualized analysis from 1990 to 2021.

Background: Coronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac requirements, which has aroused wide concerns in basic science and clinical cardiovascular research. We aimed to analyze coronary microcirculation-associated literatures over 30 years and provide insightful information on the evolutionary path, frontier research hotspots, and future developmental trends. Methods: Publications were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer was used to perform co-occurrence analyses for countries, institutions, authors, and keywords and to generate visualized collaboration maps. CiteSpace was used to visualize the knowledge map derived from reference co-citation analysis, burst references, and keywords detection. Results: This analysis was performed based on 11,702 publications including 9981 articles and 1721 reviews. The United States and Harvard University ranked at the top among all the countries and institutions. The majority of articles were published in Circulation, and it also was the most co-cited journal. Thematic hotspots and frontiers were focused on coronary microvascular dysfunction, magnetic resonance imaging, fractional flow reserve, STEMI, and heart failure. Additionally, keywords burst and co-occurrence cluster analysis showed that management, microvascular dysfunction, microvascular obstruction, prognostic value, outcomes, and guidelines were current knowledge gaps and future directions. Conclusions: Coronary microcirculation presented a research hotspot relevant wide spectrum of cardiovascular diseases. Definite diagnostics and prognostics are particularly valued. The protection of cardiovascular events that influence clinical outcomes should be an insightful concern in the future. Multidisciplinary collaborations will provide significant advances for the development of coronary microcirculation.

Mass Cytometry Reveals the Imbalanced Immune State in the Peripheral Blood of Patients with Essential Hypertension.

Mounting evidence has confirmed that essential hypertension (EH) is closely related to low-grade inflammation, but there is still a lack of in-depth understanding of the state of immune cells in the circulating blood of patients with EH. We analyzed whether hypertensive peripheral blood immune cell balance was destroyed. The peripheral blood mononuclear cells (PBMCs) of all subjects were analyzed using time-of-flight cytometry (CyTOF) based on 42 kinds of metal-binding antibodies. CD45+ cells were categorized into 32 kinds of subsets. Compared with the health control (HC) group, the percentage of total dendritic cells, two kinds of myeloid dendritic cell subsets, one intermediate/nonclassical monocyte subset and one CD4+ central memory T cell subset in the EH group, was significantly higher; the percentage of low-density neutrophils, four kinds of classical monocyte subsets, one CD14lowCD16- monocyte subset, one naive CD4+ and one naive CD8+ T cell subsets, one CD4+ effector and one CD4+ central memory T cell subsets, one CD8+ effector memory T cell subset, and one terminally differentiated γδ T cell subset, decreased significantly in EH. What is more, the expression of many important antigens was enhanced in CD45+ immune cells, granulocytes, and B cells in patients with EH. In conclusion, the altered number and antigen expression of immune cells reflect the imbalanced immune state of the peripheral blood in patients with EH.

Global trend and future landscape of intestinal microcirculation research from 2000 to 2021: A scientometric study.

BACKGROUND: The intestinal microcirculation functions in food absorption and metabolic substance exchanges. Accumulating evidence indicates that intestinal microcirculatory dysfunction is a significant source of multiple gastrointestinal diseases. To date, there has not been a scientometric analysis of intestinal microcirculatory research. AIM: To investigate the current status, development trends, and frontiers of intestinal microcirculatory research based on bibliometric analysis. METHODS: VOSviewer and CiteSpace 6.1.R2 were used to identify the overall characteristics and knowledge map of intestinal microcirculatory research based on the core literature published from 2000 to 2021 in the Web of Science database. The characteristics of each article, country of origin, institution, journal, cocitations, and other information were analyzed and visualized. RESULTS: There were 1364 publications enrolled in the bibliometric analysis, exhibiting an upward trend from 2000 to 2021 with increased participation worldwide. The United States and Dalhousie University took the lead among countries and institutions, respectively. Shock was the most prolific journal, and Nature Reviews Microbiology Clinical had the most citations. The topical hotspots and frontiers in intestinal microcirculatory research were centered on the pathological processes of functional impairment of intestinal microvessels, diverse intestinal illnesses, and clinical treatment. CONCLUSION: Our study highlights insights into trends of the published research on the intestinal microcirculation and offers serviceable guidance to researchers by summarizing the prolific areas in intestinal disease research to date.

Long non-coding RNA LINC01128 affects proliferation, migration, and invasion of glioma cells by regulating miR-27b-3p.

INTRODUCTION: Glioma is a collective term for tumors derived from glial cells and neuronal cells in the nervous system, and is the most common malignant tumor in the brain. Nowadays, the problem of poor treatment effect and high recurrence rate of patients remains to be solved. MATERIAL AND METHODS: In this study, the expression levels of LINC01128 in glioma tissues, cells, and normal control group were determined by real-time quantitative PCR (RT-qPCR). Kaplan-Meier curve was used to evaluate the prognosis and survival. Multivariate Cox analysis was chosen to estimate the prognostic risk factors of glioma. Cell counting kit-8 (CCK-8) and Transwell methods were used to detect the effect of silencing LINC01128 on the proliferation, migration, and invasion of glioma cells, and the targeting effect of LINC01128 on miR-27b-3p was determined based on bio-informatics analysis and luciferase activity detection. RESULTS: LINC01128 was up-regulated in glioma tissues and cells. The possibility of LINC01128 as a prognostic factor of glioma was obtained through Kaplan-Meier's clinical data analysis and multivariate Cox analysis. Silencing LINC01128 targeting miR-27b-3p inhibited the proliferation, migration, and invasion activity of glioma cells. Moreover, there was a negative correlation between LINC01128 and miR-27b-3p. CONCLUSIONS: Silencing LINC01128 inhibited the proliferation, migration, and invasion levels of glioma cells by targeting miR-27b-3p, thereby affecting the progression of gliomas.

Role of insulin in pancreatic microcirculatory oxygen profile and bioenergetics.

BACKGROUND: The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery. In diabetes, the balance between oxygen delivery and consumption is impaired. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity. AIM: To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics. METHODS: The pancreatic microcirculatory partial oxygen pressure (PO2), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO2) were evaluated in nondiabetic, type 1 diabetes mellitus (T1DM), and insulin-treated mice. A three-dimensional framework was generated to visualize the microcirculatory oxygen profile. Ultrastructural changes in the microvasculature were examined using transmission electron microscopy. An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells (IMECs). RESULTS: Significantly lower PO2, rHb, and SO2 values were observed in T1DM mice than in nondiabetic controls. Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs. Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity. Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs (P < 0.05). An energy map revealed increased energetic metabolism in insulin-treated IMECs, with significantly increased ATP production, non-mitochondrial respiration, and oxidative metabolism (all P < 0.05). Significant negative correlations were revealed between microcirculatory SO2 and bioenergetic parameters. CONCLUSION: Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.

Sodium Pentobarbital Suppresses Breast Cancer Cell Growth Partly via Normalizing Microcirculatory Hemodynamics and Oxygenation in Tumors.

Breast cancer remains the leading cause of cancer-related death among women worldwide. Sodium pentobarbital was found to play an inhibitory role in glioma growth in rats. In this study, we aimed to evaluate the effects of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and its impacts on the microcirculatory changes on both skin and tumor surface in mice bearing subcutaneous xenograft. Cell counting assay was used to assess the antiproliferative effect of sodium pentobarbital on MDA-MB-231 breast cancer cells. Subcutaneous xenograft model was established to study the role of sodium pentobarbital on in vivo tumor growth. Speed-resolved blood perfusion, hemoglobin oxygen saturation (SO2, %), total hemoglobin tissue concentration (ctTHb, µM), and red blood cell (RBC) tissue fraction (%) were examined simultaneously by using enhanced perfusion and oxygen saturation system to investigate the effects of sodium pentobarbital on microcirculatory hemodynamics and oxygenation. Sodium pentobarbital suppressed breast tumor growth both in vitro and in vivo. Cutaneous blood flux in nutritive capillaries with low-speed flow was significantly increased in tumor-bearing mice, and high-dose sodium pentobarbital treatment cause a reduction in this low-speed blood flux, whereas sodium pentobarbital therapy caused an elevated blood flux in larger microvessels with mid and high speed in a dose-dependent manner. Different doses of sodium pentobarbital exerted different actions on SO2, ctTHb, and RBC tissue fraction. Collectively, the inhibitory effect of sodium pentobarbital on breast tumor growth was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors. SIGNIFICANCE STATEMENT: This study is the first to demonstrate the inhibiting effect of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and such an inhibition was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors.

Lymphatic microcirculation profile in the progression of hypertension in spontaneously hypertensive rats.

OBJECTIVE: The contractile behavior of collecting lymphatic vessels occurs in essential hypertension in response to homeostasis, suggesting a possible role for microcirculation. We aimed to clarify the nature of the lymphatic microcirculation profile in spontaneously hypertensive rats (SHRs) and normotensive controls. METHODS: The vasomotion of collecting lymphatic vessels in eight- and thirteen-week-old SHRs and age-matched Wistar-Kyoto rats (WKYs, n = 4 per group) was visualized by intravital video and VasTrack. The lymphatic vasomotion profile (frequency and amplitude) and contractile parameters (contraction fraction and total contractility activity index) were compared. Plasma nitrite/nitrate levels were assessed by the Griess reaction, and plasma endothelin-1 was measured by enzyme-linked immunosorbent assay. RESULTS: WKYs and SHRs differed in the vasomotion of collecting lymphatic vessels. Both eight- and thirteen-week-old WKYs revealed a high-amplitude pumping pattern, whereas a low-amplitude pattern was observed in SHRs. Moreover, compared with age-matched WKYs, SHRs exhibited deteriorated output and reflux capability and lost the ability to regulate collecting lymphatic vasomotion. Additionally, the chemistry complements the microcirculatory lymphatic profile as demonstrated by an increase in plasma nitrite, nitrate, and endothelin-1 in SHRs. ET-1 inhibitor meliorated the lymphatic contractile capability in SHRs partially through regulating frequency of lymphatic vasomotion. CONCLUSIONS: We used an intravital lymphatic imaging system to observe that SHRs exhibit an impaired collecting lymphatic vasomotion profile and deteriorated contractility and reflux.

Roquin2 suppresses breast cancer progression by inhibiting tumor angiogenesis via selectively destabilizing proangiogenic factors mRNA.

Tumor angiogenesis is an essential step in tumor growth and metastasis. The initiation of tumor angiogenesis is dictated by a shift in the balance between proangiogenic and antiangiogenic gene expression programs. Roquin2 is a zinc-finger RNA-binding protein with important roles in mediating the expression of inflammatory genes, such as TNF, IL6 and PTGS2, which are also important angiogenic factors. In this study, we demonstrate that Roquin2 functions as a potent tumor angiogenesis regulator that inhibits breast tumor-induced angiogenesis by selectively destabilizing mRNA of proangiogenic gene transcripts, including endoglin (ENG), endothelin-1 (EDN1), vascular endothelial growth factor B (VEGFB) and platelet derived growth factor C (PDGFC). Roquin2 recognizes and binds the stem-loop structure in the 3'untranslated region (3'UTR) of these mRNAs via its ROQ domain to destabilize mRNA. Moreover, we found that Roquin2 expression was reduced in breast cancer cells and tissues, and associated with poor prognosis in breast cancer patients. Overexpression of Roquin2 inhibited breast tumor-induced angiogenesis in vitro and in vivo, whereas silencing Roquin2 enhanced tumor angiogenesis. In vivo induction of Roquin2 by adenovirus significantly suppressed breast tumor growth, metastasis and angiogenesis. Taken together, our results identify that Roquin2 is a novel breast cancer suppressor that inhibits tumor angiogenesis by selectively downregulating the expression of proangiogenic genes.

Integrated pancreatic microcirculatory profiles of streptozotocin-induced and insulin-administrated type 1 diabetes mellitus.

OBJECTIVE: As an integrated system, pancreatic microcirculatory disturbance plays a vital role in the pathogenesis of type 1 diabetes mellitus (T1DM), which involves changes in microcirculatory oxygen and microhemodynamics. Therefore, we aimed to release type 1 diabetic and insulin-administrated microcirculatory profiles of the pancreas. METHODS: BALB/c mice were assigned to control, T1DM, and insulin-administrated groups randomly. T1DM was induced by intraperitoneal injection of streptozotocin (STZ). 1.5 IU insulin was administrated subcutaneously to keep the blood glucose within the normal range. After anesthetizing by isoflurane, the raw data set of pancreatic microcirculation was collected by the multimodal device- and computer algorithm-based microcirculatory evaluating system. After adjusting outliers and normalization, pancreatic microcirculatory oxygen and microhemodynamic data sets were imported into the three-dimensional module and compared. RESULTS: Microcirculatory profiles of the pancreas in T1DM exhibited a loss of microhemodynamic coherence (significantly decreased microvascular blood perfusion) accompanied by an impaired oxygen balance (significantly decreased PO2 , SO2 , and rHb). More importantly, with insulin administration, the pathological microcirculatory profiles were partially restored. Meanwhile, there were correlations between pancreatic microcirculatory blood perfusion and PO2 levels. CONCLUSIONS: Our findings establish the first integrated three-dimensional pancreatic microcirculatory profiles of STZ-induced and insulin-administrated T1DM.

TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs.

Tumor angiogenesis is a crucial step in the further growth and metastasis of solid tumors. However, its regulatory mechanism remains unclear. Here, we showed that TARBP2, an RNA-binding protein, played a role in promoting tumor-induced angiogenesis both in vitro and in vivo through degrading the mRNAs of antiangiogenic factors, including thrombospondin1/2 (THBS1/2), tissue inhibitor of metalloproteinases 1 (TIMP1), and serpin family F member 1 (SERPINF1), by targeting their 3'untranslated regions (3'UTRs). Overexpression of TARBP2 promotes tumor cell-induced angiogenesis, while its knockdown inhibits tumor angiogenesis. Clinical cohort analysis revealed that high expression level of TARBP2 was associated with poor survival of lung cancer and breast cancer patients. Mechanistically, TARBP2 physically interacts with the stem-loop structure located in the 3'UTR of antiangiogenic transcripts, leading to mRNA destabilization by the dsRNA-binding domains 1/2 (dsRBDs1/2). Notably, the expression level of TARBP2 in human tumor tissue is negatively correlated with the expression of antiangiogenic factors, including THBS1/2, and brain-specific angiogenesis inhibitor 1 (BAI1). Moreover, TARBP2 expression is strongly associated with tumor angiogenesis in a group of human lung cancer samples. Collectively, our results highlight that TARBP2 is a novel tumor angiogenesis regulator that could promote tumor angiogenesis by selectively downregulating antiangiogenic gene expression.

Ovarian cancer derived PKR1 positive exosomes promote angiogenesis by promoting migration and tube formation in vitro.

Cancer cell derived exosomes play important roles in cancer progression and modulation of the tumour microenvironment. This study aims to investigate the role of prokineticin receptor 1 (PKR1) positive exosomes on angiogenesis. In the present study, PKR1 expression in tumour samples from ovarian cancer patients were examined firstly. Then, two ovarian cancer cell lines, namely A2780 and HO-8910 cells, were used to isolate and obtain the PKR1 positive exosomes from the serum free medium. The function analysis of PKR1 positive exosomes on angiogenesis was conducted by cell proliferation and migration assay, tube formation analysis, and tumour volume assay. The results showed that PKR1 expression was down regulated in tumour samples of ovarian cancer patients compared with adjacent normal tissues. The intracellular expression of PKR1 could be detected in A2780 and HO-8910 cells. And, the isolated exosomes from the serum free medium were confirmed by transmission electron microscopic and NTA analysis, as well as the co-presence of PKR1 with exosome marker CD63. The function analysis of PKR1 positive exosomes on angiogenesis demonstrated the uptake of PKR1 positive exosomes by human umbilical vein endothelial cells through immunofluorescence staining. The angiogenesis assays in vitro indicated that PKR1 positive exosomes promoted migration and tube formation of HUVECs but not proliferation. The endogenous PKR1 was also verified to help to enhance migration and promote tube formation of vascular endothelial cells, which might involved in the phosphorylation of STAT3. Additionally, The tumour volume from exosomes treated A2780 tumour-bearing mice was significantly increased compared with the control group, accompanied with the induced PKR1 expression and phosphorylation of STAT3 level. SIGNIFICANCE OF THE STUDY: This study proved the important role of PKR1 positive exosomes released from ovarian cancer cells on promoting angiogenesis. The data indicated that PKR1 derived from ovarian cancer cells could act as an important tumour associated antigen and biomolecular factor for cellular communication in tumour microenvironment.

Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle-promoting genes.

BACKGROUND: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer. METHODS: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1. RESULTS: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle-promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem-loop structure in the 3' untranslated region (3'UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle-promoting mRNAs. CONCLUSIONS: Our findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle-promoting genes, which might be a potential molecular target for breast cancer treatment.

Diagnostic value of miR-186-5p for carotid artery stenosis and its predictive significance for future cerebral ischemic event.

BACKGROUND: MicroRNAs (miRNAs) serve as novel promising biomarkers for the diagnosis and prognosis of many human diseases. This study investigated the diagnostic value of miR-186-5p for asymptomatic carotid artery stenosis (CAS), and its predictive value for future cerebral ischemic events (CIEs). METHODS: Sixty-seven cases with asymptomatic CAS and 60 healthy individuals were recruited. Serum levels of miR-186-5p were tested by using qRT-PCR. Receiving-operator characteristic (ROC) curve was drawn based on sensitivity and specificity analyses. All asymptomatic CAS cases were followed up for 5 years. Kaplan-Meier method was applied for the evaluation of the predictive value of miR-186-5p for the occurrence of CIE. RESULTS: The serum level of miR-186-5p was increased significantly in asymptomatic CAS patients. MiR-186-5p was the most significant factor associated with the high degree of carotid stenosis in asymptomatic CAS patients. In the ROC curve analysis, the AUC was 0.919, with the sensitivity of 89.6% and specificity of 81.7% at the cutoff value of 1.221. Kaplan-Meier method results revealed that high miR-186-5p level was associated with the occurrence of CIEs. High miR-186-5p level and high degree of carotid stenosis were independent factors for the occurrence of CIEs. CONCLUSION: MiR-186-5p serves as a potential diagnostic biomarker for patients with asymptomatic CAS, and predicts the occurrence of future CIEs.