Transcriptomic analysis reveals Cilostazol's role in ameliorating cardiovascular disease: Inhibition of monocyte-to-macrophage differentiation and reduction of endothelial cell reactive oxygen species production.

Background: Cardiovascular diseases (CVDs) are the leading global cause of death, with atherosclerosis as the primary cause. Chronic inflammation, endothelial dysfunction, and the role of molecules like nitric oxide and reactive oxygen species are crucial in this context. Our previous research indicated that cilostazol and ginkgo biloba extract could enhance the ability of endothelial cells to dissolve blood clots, but the effects of cilostazol on monocytes remain unexplored. Method: This study utilized peripheral blood mononuclear cells from 10 healthy donors, treated ex vivo with cilostazol. RNA-sequencing, over-representation analysis, xCell stromal cell analysis, and Gene Set Enrichment Analysis were employed to investigate the gene expression changes and biological pathways affected by cilostazol treatment. Results: The study identified specific gene sets and pathways that were enriched or reduced in response to cilostazol treatment, providing insights into its effects on monocytes and potential therapeutic applications in CVD. The analysis also revealed the potential impact of cilostazol on the stromal cell compartment, further broadening our understanding of its multifaceted role. Conclusion: The findings offer a nuanced understanding of the advantages and mechanisms of cilostazol in CVD, uncovering novel therapeutic targets and strategies to enhance the clinical application of cilostazol and contributing to the broader implications of this therapy in cardiovascular health.

Elucidating the Associated Biological Function and Clinical Significance of RHOJ Expression in Urothelial Carcinoma.

Urothelial cancer, a common urinary system malignancy, often presents treatment challenges due to metastasis and chemotherapy side effects. Angiogenesis, crucial for tumor growth, has become a target for drug development. This study explores the expression, prognostic value, and clinical correlation of RHOJ in the TCGA BLCA, GSE31684, and GSE32894 datasets. We identify common differentially expressed genes across these databases and utilize g:Profiler and Cytoscape ClueGO for functional assessment. Further, we perform a gene set enrichment analysis (GSEA) using Hallmark gene sets and use the imsig package for immune cell infiltration analysis. Our analysis indicates that RHOJ expression levels significantly impact survival rates, tumor progression, and immune response in urothelial tumors. High RHOJ expression correlated with poor prognosis, advanced disease stages, and an increase in monocyte population within the tumor microenvironment. This aligns with current literature indicating a key role of immune infiltration in bladder cancer progression and treatment response. Moreover, the GSEA and imsig results further suggest a potential mechanistic link between RHOJ expression and immune-related pathways. Considering the increasing emphasis on immunotherapeutic strategies in bladder cancer management, our findings on RHOJ's potential as a diagnostic biomarker and its association with immune response open new avenues for therapeutic interventions.

Profiling of miRNAs and their interfering targets in peripheral blood mononuclear cells from patients with chronic myeloid leukaemia.

Introduction: MicroRNAs may be implicated in the acquisition of drug resistance in chronic myeloid leukemia as they regulate the expression of not only BCR-ABL1 but also genes associated with the activation of drug transfer proteins or essential signaling pathways. Methods: To understand the impact of specifically expressed miRNAs in chronic myeloid leukemia and their target genes, we collected peripheral blood mononuclear cells (PBMC) from patients diagnosed with chronic myeloid leukemia (CML) and healthy donors to determine whole miRNA expression by small RNA sequencing and screened out 31 differentially expressed microRNAs (DE-miRNAs) with high expression. With the utilization of miRNA set enrichment analysis tools, we present here a comprehensive analysis of the relevance of DE-miRNAs to disease and biological function. Furthermore, the literature-based miRNA-target gene database was used to analyze the overall target genes of the DE-miRNAs and to define their associated biological responses. We further integrated DE-miRNA target genes to identify CML miRNA targeted gene signature singscore (CMTGSS) and used gene-set enrichment analysis (GSEA) to analyze the correlation between CMTGSS and Hallmark gene-sets in PBMC samples from clinical CML patients. Finally, the association of CMTGSS stratification with multiple CML cell lineage gene sets was validated in PBMC samples from CML patients using GSEA. Results: Although individual miRNAs have been reported to have varying degrees of impact on CML, overall, our results show that abnormally upregulated miRNAs are associated with apoptosis and aberrantly downregulated miRNAs are associated with cell cycle. The clinical database shows that our defined DE-miRNAs are associated with the prognosis of CML patients. CMTGSS-based stratification analysis presented a tendency for miRNAs to affect cell differentiation in the blood microenvironment. Conclusion: Collectively, this study defined differentially expressed miRNAs by miRNA sequencing from clinical samples and comprehensively analyzed the biological functions of the differential miRNAs in association with the target genes. The analysis of the enrichment of specific myeloid differentiated cells and immune cells also suggests the magnitude and potential targets of differentially expressed miRNAs in the clinical setting. It helps us to make links between the different results obtained from the multi-faceted studies to provide more potential research directions.

Assessment and driving factor of housing vacancies in Shandong Peninsula urban agglomeration based on multi-source remote sensing data.

As the urbanization rate in the world has increased rapidly, the housing vacancy problem has become serious and attracting more attention. Calculating and analyzing vacant housing can help reduce the wasteful use of resources. This paper measures the housing vacancy rate and housing vacancy stock in the Shandong Peninsula urban agglomeration using night-time lighting and land use data. The results show that the average housing vacancy rate in the Shandong Peninsula urban agglomeration rose rapidly from 14.68% in 2000 to 29.71% in 2015 before declining slowly to 29.49% in 2020. Since urban population growth is lower than the housing construction rate, the average annual growth of housing vacancy stock between 2000 and 2020 exceeds 3 million square meters in megacities and is around 1-2 million square meters in large and medium-sized cities. The vacant housing has caused considerable waste of housing resources. The driving factors of the housing vacancy were further analyzed using the LMDI decomposition method. Results indicate that the economic development level is the most significant driving factor of the vacant housing stock. In addition, the value effect of unit floor areas is the major driving factor inhibiting the growth of vacant housing stock, while the decline of unit floor area value is conducive to the reduction of this stock.

Structure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer.

The C-X3-C motif chemokine ligand (CX3CL)1 (also known as Fractalkine) and its receptor CX3CR1 (also known as G-protein coupled receptor 13) are expressed on the membranes of many different cells such as epithelial cells, dendritic cells, smooth muscle cells, and neurons. CX3CR1 is primarily expressed on monocytes, macrophages, dendritic cells, T cells, and natural killer cells. The binding of CX3CL1 to CX3CR1 induces the activation of heterotrimeric G proteins associated with this receptor. In addition, it triggers the signal pathways of MAPK and AKT, which play essential roles in tumour biology. Mechanistically, the CX3CL1-CX3CR1 axis has an antitumour role by recruiting antitumoural immune cells such as NK cells and T cells into the tumour microenvironment to control tumour growth. On the other hand, accumulated evidence indicates that the CX3CL1-CX3CR1 axis also activates a pro-tumoral response. This review will focus on the unique structural biology features of CX3CL1 and CX3CR1, their interactions in tumour inflammatory response, and antitumour effects, which highlights possible potential therapeutic targets.

Jumps and stock market variance during the COVID-19 pandemic: Evidence from international stock markets.

Based on the work of Buncic and Gisler (2017), this paper investigates whether the roles of jump components will change in forecasting the volatility of international equity markets during the COVID-19 pandemic. Interestingly, in contrast to the conclusions of Buncic and Gisler (2017), we find jump components of the international equity indices are useful to predict the international stock markets' volatility during the COVID-19 pandemic. Our study tries to provide new evidence of jump components in stock markets.

Structure and Functions of T-cell Immunoglobulin-domain and Mucin- domain Protein 3 in Cancer.

BACKGROUND: T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling. METHODS: This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types and the rationale for TIM-3-targeted cancer immunotherapy. RESULTS: TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models. CONCLUSION: TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.

OX40 and OX40L Interaction in Cancer.

BACKGROUND: OX40 (CD134) and its binding partner, OX40L (CD252), are expressed on activated CD4, CD8 T-cells, and several other lymphoid and non-lymphoid cells. OX40L belongs to a TNF family member, a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L is a trimeric contableuration of one OX40L (trimer) and three OX40 monomers. OX40 and OX40L regulate cytokine production from T-cells, antigen-presenting cells, and natural killer (NK) cells, and modulate cytokine receptor signaling. METHODS: In this review, an updated overview of the structural features of OX40/OX40L and their interactions with cancer are provided. RESULTS: Recent studies have shown that stimulation of OX40 is useful for therapeutic immunization strategies for cancer. OX40 serves as a secondary costimulatory immune checkpoint molecule; the binding of OX40 to its ligand enhances the augmentation, survival, memory formation, effector function, and recall responses of both CD4+ and CD8+ T-cells. CONCLUSION: This review highlights that OX40-OX40L interactions play crucial roles in both CD4+ and CD8+ T-cells. Signals through OX40 can abolish the suppressive activity of Tregs, prevent the induction of Tregs from effector T-cells, reduce Foxp3 expression, and induce the proliferation of memory and effector T lymphocytes. Additionally, when transferred into tumor-bearing recipients, they generate proliferation capability and successfully eliminate the established tumor.

Examining the predictive information of CBOE OVX on China's oil futures volatility: Evidence from MS-MIDAS models.

This study evaluates whether CBOE crude oil volatility index (OVX) owns forecasting ability for China's oil futures volatility using Markov-regime mixed data sampling (MS-MIDAS) models. In-sample empirical result shows that, OVX can significantly lead to high future short-term, middle-term and long-term volatilities with regard to Chinese oil futures market. Moreover, our proposed model, the Markov-regime MIDAS with including the OVX (MS-MIDAS-RV-OVX), significantly outperforms the MIDAS and other competing models. Unsurprising results further confirm that OVX indeed contain predictive information for oil realized volatility (especially significant and robust in middle-term and long-term horizons) and regime switching is useful to deal with the structural break within the energy market. We carry out economic value analysis and discuss OVX's asymmetric effects concerning different trading hours and good (bad) OVX, and find OVX performs better in day-time trading hours and the good OVX is more predictive for the oil futures RV than the bad OVX. The further discussion also confirms our previous conclusions are robust during the highly volatile period of the COVID-19 pandemic.

Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis.

BACKGROUND: Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism. METHOD: A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis. RESULTS: Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects. CONCLUSION: ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.

Which popular predictor is more useful to forecast international stock markets during the coronavirus pandemic: VIX vs EPU?

This study mainly investigates which predictors (VIX or EPU index) are useful to forecast future volatility for 19 equity indices based on HAR framework during coronavirus pandemic. Out-of-sample analysis shows that the HAR-RV-VIX model exhibits superior forecasting performance for 12 stock markets, while EPU index just can improve forecast accuracy for 5 equity indices, implying that VIX index is more useful for most stock markets' future volatility during coronavirus crisis. The results are robust in recursive window method, alternative realized measures and sub-sample analysis; moreover, VIX index still contains the strongest predictive ability by considering kitchen sink model and mean combination forecast. Furthermore, we further discuss the predictive effect of VIX and EPU index before the coronavirus crisis. Our article provides policy makers, researchers and investors with new insights into exploiting the predictive ability of VIX and EPU index for international stock markets during coronavirus pandemic.

The Role of Large Neutral Amino Acid Transporter (LAT1) in Cancer.

BACKGROUND: The solute carrier family 7 (SLC7) can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino acids by facilitating diffusion with intracellular substrates. LAT1 (also known as SLC7A5), is defined as a heteromeric amino acid transporter (HAT) interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide to uptake not only large neutral amino acids, but also several pharmaceutical drugs to cells. METHODS: In this review, we provide an overview of the interaction of the structure-function of LAT1 and its essential role in cancer, specifically, its role at the blood-brain barrier (BBB) to facilitate the transport of thyroid hormones, pharmaceuticals (e.g., I-DOPA, gabapentin), and metabolites into the brain. RESULTS: LAT1 expression increases as cancers progress, leading to higher expression levels in highgrade tumors and metastases. In addition, LAT1 plays a crucial role in cancer-associated reprogrammed metabolic networks by supplying tumor cells with essential amino acids. CONCLUSION: The increasing understanding of the role of LAT1 in cancer has led to an increase in interest surrounding its potential as a drug target for cancer treatment.

Long-Term Efficacy and Safety of Immunomodulatory Therapy for Atherosclerosis.

BACKGROUND AND AIMS: The long-term effect of immune tolerance has not been explored so far in atherosclerosis. In the present study, we assessed the effect of mucosal tolerance to a multi antigenic construct expressing three peptides from ApoB, HSP60, and outer membrane protein from Chlamydia pneumonia (AHC) for 30 weeks at every 6-week interval to understand the kinetics of immune modulation in disease progression. The safety profile of the molecule was also evaluated in mice. METHODS: Apobtm2SgyLdlrtm1Her/J mice (5-6 weeks) were orally dosed with multi antigenic construct (AHC) molecule on alternate days, followed by high-fat diet feeding to initiate atherosclerosis. RESULTS: Treated animals showed an efficient reduction in plaque growth and lipid accumulation at 6 weeks (49%, p < 0.01) and 12 weeks (42.3%, p < 0.01) which decreased to 29% (p = 0.0001) at 18 weeks and at later time points. Macrophage accumulation was significantly lower at all time points (53% at 12 weeks to 27% at 30 weeks). Regulatory T cells increased in the spleen following treatment until 12 weeks (week 0 (2.57 ± 0.18 vs. 6.36 ± 0.03, p = 0.02), week 6 (4.52 ± 0.2 vs. 8.87 ± 0.32, p = 0.02), and week 12 (8.74 ± 0.37 vs. 15.4 ± 0.27, p = 0.02)) but showed a decline later. A similar trend was observed with tolerogenic dendritic cells. We observed an increase in antibody levels to low-density lipoprotein and oxidized LDL at later stages. AHC molecule was found to be safe in acute and repeated dose toxicity studies. CONCLUSIONS: Our results suggest that immune tolerance to AHC protein by oral administration is able to provide efficient atheroprotection up to 18 weeks and moderately at later stages. Apart from immune regulatory cells, protective antibodies may also have a role in controlling atherosclerosis.

Structure and Function of Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) in Hyperlipidemia and Atherosclerosis.

BACKGROUND: One of the important factors in Low-Density Lipoprotein (LDL) metabolism is the LDL receptor (LDLR) by its capacity to bind and subsequently clear cholesterol derived from LDL (LDL-C) in the circulation. Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is a newly discovered serine protease that destroys LDLR in the liver and thereby controls the levels of LDL in plasma. Inhibition of PCSK9-mediated degradation of LDLR has, therefore, become a novel target for lipid-lowering therapy. METHODS: We review the current understanding of the structure and function of PCSK9 as well as its implications for the treatment of hyperlipidemia and atherosclerosis. RESULTS: New treatments such as monoclonal antibodies against PCSK9 may be useful agents to lower plasma levels of LDL and hence prevent atherosclerosis. CONCLUSION: PCSK9's mechanism of action is not yet fully clarified. However, treatments that target PCSK9 have shown striking early efficacy and promise to improve the lives of countless patients with hyperlipidemia and atherosclerosis.

Author Correction: Immune regulation by oral tolerance induces alternate activation of macrophages and reduces markers of plaque destabilization in Apobtm2Sgy/Ldlrtm1Her/J mice.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Chlamydia pneumoniae Infection Exacerbates Atherosclerosis in ApoB100only/LDLR-/- Mouse Strain.

AIMS: Hyperlipidaemia model animals have been used to elucidate the role of Chlamydia pneumoniae (Cpn) infection in atherosclerosis. The aims of this study were to investigate the proatherogenic effect of multiple Cpn infections in ApoB100only/LDLR-/- mice which based on lipid profile can be regarded as the most suitable mouse model of human hypercholesterolemia and to compare the lesion development to that in a major atherosclerosis model ApoE-/- mice. METHODS AND RESULTS: Aorta samples of ApoB100only/LDLR-/- mice infected three times with Cpn were subjected to morphometric analyses. Morphometric evaluation disclosed that Cpn infections exacerbated atherosclerosis development in the aortic root and descending aorta of the mice fed with normal diet. Viable Cpn was detected in the ascending aorta by RT-PCR. Chlamydial 16SrRNA expression showed the presence of viable Cpn in the aorta of infected animals. A similar rate of acceleration of atherosclerosis was observed when the infection protocol was applied in ApoB100only/LDLR-/- and in ApoE-/- mice. CONCLUSION: Similar to ApoE-/- mice, ApoB100only/LDLR-/- mice with more human-relevant serum lipoprotein composition develop increased atherosclerosis after Cpn infections; thus this mouse strain can be used as a model of infection-related atherosclerosis enhancement and can provide further evidence for the proatherogenic influence of Cpn in mice.

Pitavastatin up-regulates eNOS production by suppressing miR-155 expression in lipopolysaccharide-stimulated human umbilical vein endothelial cells.

AIM: Pitavastatin (Pit) has been proved to efficiently inhibit the onset and progression of atherosclerosis. However, the mechanism by which Pit exerts nonlipid-related effects, such as antiinflammatory actions, is not quite clear. Our study aimed at investigating the effect of Pit on the expression of endothelial NO synthase (eNOS) and miR-155 in LPS-stimulated HUVECs to reveal the antiinflammatory mechanism of pitavastatin. METHODS: HUVECs were isolated from newborn umbilical cords and used in the experiments at passages 2-5. Cells were treated with LPS (0.05, 0.1, 1 µg/L) or LPS (0.1 µg/L)+Pit (0.01, 0.1, 1 µmol/L), untreated cells were used as control. For LPS+Pit induction, cells were firstly incubated with Pit for 1 hour before coincubation with LPS for 24 hours. eNOS mRNA and miR-155 were detected by RT-PCR, and Western blotting was used to detect protein expression of eNOS. RESULTS: Treatment of HUVECs with LPS enhanced the expression of miR-155 and reduced the expression of eNOS in mRNA and protein level in a dose-dependent manner as revealed by RT-PCR and Western blotting, respectively. Pitavastatin ameliorated LPS-induced endothelial dysfunction through upregulation of eNOS expression and downregulation of miR-155 expression. CONCLUSION: Pitavastatin increases eNOS expression and inhibits of LPS-induced miR-155 expression.

Immune regulation by oral tolerance induces alternate activation of macrophages and reduces markers of plaque destabilization in Apobtm2Sgy/Ldlrtm1Her/J mice.

Atherosclerosis is the leading cause for cardiovascular mortality. We determined the effect of multi-antigenic construct expressing three peptides AHC (ApoB100, HSP60 and outer membrane protein of chlamydia pneumonia) in stabilizing advanced atherosclerosis in Apobtm2Sgy/Ldlrtm1Her/J mice. Atherosclerosis was induced by feeding high fat diet (HFD) to mice for 10 weeks, followed by five oral dosing with purified AHC or ovalbumin on alternate days and continued on HFD for another 10 weeks. Tolerance was associated with significantly higher numbers of regulatory T cells both in aortic sinus and spleen with higher mRNA expression of CTLA4 (3 fold), Foxp3 (1.4 folds) and TGF-ß (1.62) in aorta. Tregs cells were found to induce alternate activation of macrophages to M2 phenotype, with a reduction in plaque inflammation. AHC treatment showed evidence of plaque stabilization as observed by reduction in plaque necrosis in aortic sinus (35.8%) and in brachiocephalic artery (26%), with reduced expression of Tissue factor and MMP9. Macrophage apoptosis was reduced and collagen content was enhanced by treatment. Our results suggest that tolerance to atherogenic peptides increases regulatory T cells which activate M2 macrophages, prevent T cell proliferation and reduce plaque destabilization and inflammatory markers thus providing evidences for plaque stabilization in mice with advanced atherosclerosis.

Impact of IL-12 in Cancer.

BACKGROUND: Interleukin 12 (IL-12) is a pleiotropic cytokine that plays an essential role in Th1-type immune response against cancer, a condition where cells in a particular part of the body grow and reproduce uncontrollably. METHODS: In this review, we describe the structural features of IL-12 family and their roles involved in cancer. RESULTS: IL-12 has been demonstrated to regulate both innate (natural killer cells) and adaptive (cytotoxic T lymphocytes) immunities in cancer therapy. This cytokine has been proposed as a potential new agent to be developed in cancer immunotherapy studies due to its impressive antitumor effects in many animal models. In addition, the antitumor activity of IL-12 can be efficiently induced by itself as well as significantly improved by its combination with various treatment modalities including antibodies, antiangiogenic agents, radiotherapy, adoptive therapy, and anti-tumor vaccines. CONCLUSION: IL-12 has potential roles in anticancer therapy. The advantages of using immunotherapeutic approaches in clinical trials have been reported recently. However, the mechanisms to underlay the immunoregulation and antitumor activities of IL-12 itself, as well as its combination, remain under investigation.

The Role of Exosomes and Exosome-derived microRNAs in Atherosclerosis.

BACKGROUND: Atherosclerosis is the leading cause of death and morbidity throughout industrialized nations, accounting for one-fifth of all deaths globally. Exosomes are bi-lipid membranous vesicles containing protein, lipid and nucleic acid contents that are released from the cells via the endolysosomal pathway. Exosomes are derived from several cells including macrophages, dendritic cells, platelets as well as human serum. METHODS: In this review, an overview of recent advances, the evidence for the role of exosomes and exosomederived microRNAs (miRNAs) in atherosclerosis are provided. RESULTS: Recent evidence has shown that exosomes derived from the cells mentioned above are involved in atherosclerosis, whose secretion appears to be regulated by various natural and experimental stimuli, physiological and pathological processes. CONCLUSION: Exosomes are now accepted as specifically secreted vesicles that enable intercellular communications and have become exponentially interesting to be used as the possible relevant biomarkers in disease development such as cadiovascular disease, particular in atherosclerosis in addition to their minimally invasive clinical diagnosis.