Process Of Angiogenesis Research Articles

Sclerotic zone in femoral head necrosis: from pathophysiology to therapeutic implications.

This review summarizes the sclerotic zone's pathophysiology, characterization, formation process, and impact on femoral head necrosis. The sclerotic zone is a reaction interface formed during the repair of femoral head necrosis. Compared with normal bone tissue, the mechanical properties of the sclerotic zone are significantly enhanced. Many factors influence the formation of the sclerotic zone, including mechanics, bone metabolism, angiogenesis, and other biological processes. The sclerotic zone plays an essential role in preventing the collapse of the femoral head and can predict the risk of the collapse of the femoral head. Regulating the formation of the sclerotic zone of the femoral head has become a direction worthy of study in treating femoral head necrosis.

Antiangiogenesis Activity of Indonesian Local Black Garlic (Allium Sativum ‘Solo): Experiments and Bibliometric Analysis

Cancer is still one of the leading causes of death in the world. Angiogenesis is the formation of new blood vessels, which plays a vital role in the growth of cancer cells. As a result, inhibition of proangiogenic factors such as vascular epidermal growth factor (VEGF) could be used as a cancer treatment strategy. Black garlic (BG) is processed fresh garlic (Allium sativum L.) for several days under controlled high temperature and humidity. The research aims to investigate the effect of Indonesian local BG on antiangiogenic activity through in vivo and in silico studies. The in vivo test was carried out by observing the formation of new blood vessels using the Chorio-Allantoic Membrane Assay (CAM). The in silico study was performed by docking analysis of BG bioactive compounds on the VEGF receptor (VEGFR). The results showed that ethanol extract, ethyl acetate fraction, and n-hexane fraction of BG inhibit new vessel blood formation, with n-hexane fraction having the highest efficacy. The molecular docking assay indicated some similarities in the amino acids involved in the interaction between the BG bioactive compounds and the native ligand in binding to VEGFR. This similarity may lead to interference with VEGFR resulting in angiogenesis inhibition. The study suggests that BG has the potential to be developed as an anticancer agent, which might be through the mechanism of inhibiting the angiogenesis process

Neurovascular Interaction and Exercise Training for Bone Regeneration

The nervous and vascular systems are widely distributed in the skeletal system and play an important role in bone metabolism and bone formation, respectively. Their independent impact on the skeletal system has received keen attention in bone-related research over the decade. However, the mechanism of neurovascular coupling during physiological bone remodeling and regeneration has recently been highlighted, considering the importance of spatial relationships between bone-associated skeletal nerves and blood vessels. In addition, the positive effect of exercise on the bones has been continuously emphasized, as evident by the improved number and function of skeletal nerves and blood vessels following exercise training. Skeletal nerve-vascular crosstalk and exercise training are essential for bone development and regeneration, respectively; however, the effect of exercise on neurovascular interactions has not yet been studied. This review aims to summarize the regulatory roles of the nerves and blood vessels in bone metabolism and regeneration and to highlight a combination of potential cellular processes of neurogenesis and angiogenesis in bone regeneration. Moreover, given the significance of the spatial relationship between nerves and blood vessels in bones and the role of exercise training, this review aims to discuss the potential physiological neurovascular coupling that occurs following exercise and physical activity.

Pulmonary hypertension: modern methods of treatment and ways of their long-term development.

Introduction: The purpose of this work is to review the main pathogenetic mechanisms of the development of PH, as well as modern established methods of treatment of various types of PH and to consider new, most relevant and promising possibilities of therapy for this pathology. Etiology, pathogenesis and epidemiology: In the modern structure of diseases, pulmonary hypertension plays a significant role, affecting about 1% of the population. However, each of its five main groups has its own characteristics. The causes of pulmonary hypertension can be a polyetiological violation of the processes of endotheliocyte apoptosis and angiogenesis, passive transmission of increased pressure from the left heart to the small circulatory system, chronic hypoxia, leading to vascular remodeling, and many others. In general, it is worth noting that, despite the multiplicity of etiological factors, the main pathogenetic link in the development of pulmonary hypertension is endothelial dysfunction. Treatment and promising areas of research: This article discusses the main established approaches to the treatment of pulmonary hypertension: general recommendations for patients, drugs used as supportive nonspecific therapy, as well as specific conservative and radical methods of treatment. In addition, the main modern directions of scientific research in the field of treatment of pulmonary hypertension are described. Such promising methods as the use of stem cells, gene therapy and epigenetic drugs are considered. Conclusion: Despite active research and many different drugs intended for the treatment of pulmonary hypertension, this pathological condition remains an urgent health problem. Thus, the search for new points of application of therapy and fundamentally new methods of treatment of pulmonary hypertension remains relevant to this day.

Correlation between Microvessel Density Based on CD31 Immunohistochemical Expression and Clinicopathology of Invasive Breast Carcinoma

Background
 Breast carcinoma is the most common malignancy in women worldwide. Tumor size, metastases, lymph node involvement (KGB), stage and histopathological grade are significant prognostic factors in invasive breast carcinoma. Microvessel density (MVD) assessment is used to measure angiogenesis which helps predict tumor behavior and the effect of antiangiogenic therapy. MVD is a quantitative calculation of intratumoral capillary blood vessels which reflects the results of the process of angiogenesis. The aim of this study was to analyze the relationship between MVD based on CD31 immunohistochemical expression and the clinicopathology of invasive breast carcinoma.
 
 Method
 Cross sectional analytic study with 42 samples diagnosed with invasive breast carcinoma at H. Adam Malik General Hospital Medan. MVD is the number of small blood vessels in terms of size and diameter (arterioles and venules) with a round lumen that is positively stained with CD31 at 10 large visual fields, categorized as low if <45 blood vessels/10 LPB and high if ≥45 blood vessels/10 LPB. The relationship between MVD and several clinicopathological parameters was analyzed using the Chi-Square, Fisher's Exact and Mann-Whitney tests.
 
 Results
 There was a significant relationship between tumor size (p=0.029), metastasis (p=0.014), stage (p=0.002), histopathological grade (p=0.0043), LVI (p=0.002), TILs (p=0.007). Large tumor size, metastases, high histopathological stage and grade, positive LVI and high TILs were significantly associated with MVD. However, there was no significant relationship between KGB involvement (p=0.570) and MVD.
 
 Conclusion
 MVD is significantly related to tumor size, metastases, stage, histopathological grade, LVI and TILs, and not significantly related to lymph node involvement. MVD plays a role in the angiogenesis of invasive breast carcinoma clinicopathology.

The effect of external counterpulsation on angiopoietin-1 and angiopoietin-2 levels in nondiabetic patients with refractory angina

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Health Research and Development of the Ministry of Health of Indonesia. Background External counterpulsation (ECP) is a noninvasive therapy that employs external compression on the lower extremities to augment coronary perfusion pressure. Numerous studies reported that ECP possesses potential benefits in enhancing the angiogenesis process by promoting expressions of several growth factors. Nondiabetic patients are believed to be more reliable in portraying the angiogenesis process. Unfortunately, the effect of ECP on angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) as angiogenesis markers has not been elucidated. Purpose The objective of this study is to evaluate the effect of ECP on Ang-1 and Ang-2 levels in nondiabetic patients with refractory angina. Methods This is a randomised, double-blind, sham-controlled clinical trial. Nondiabetic patients with refractory angina, who were not contraindicated to ECP therapy, were enrolled and randomised into ECP or sham groups. The treatment consisted of optimal medical therapy plus 35 sessions of ECP or sham, with an hour duration for each session. The pressure applied was up to 300 mmHg in the ECP group, while only 75 mmHg in the sham group. Subjective symptoms, laboratory, echocardiographic, and functional capacity parameters were measured before and after 35 sessions of treatment. Appropriate statistical tests were performed and a p-value of <0.05 was considered statistically significant. Results A total of 26 nondiabetic patients with refractory angina were enrolled and randomised into ECP (n=11) and sham (n=15) groups. All patients successfully followed every treatment session until the 35th session. The baseline characteristics were comparable between the two groups (p>0.05). After 35 sessions, there were increases in Ang-1 median levels in both ECP (1663.4 pg/ml versus 891.6 pg/ml, p=0.477) and sham groups (1577.0 pg/ml versus 1295.0 pg/ml, p=0.496). The Ang-2 median levels after the treatments were slightly lower in ECP (2849.5 pg/ml versus 2902.3 pg/ml, p=0.594), while higher in sham groups (2728.3 pg/ml versus 2376.2 pg/ml, p=0.826). Meanwhile, the ECP group also showed an improvement in the Canadian Cardiovascular Society (CCS) angina class from class III to class I/II in 18% (2 out of 11) patients, while in the sham group only 13% (2 out of 15) patients. Interestingly, the ECP group seemed to elicit a noticeable increase in Ang-1 median levels and a decrease in Ang-2 median levels. However, the effects of ECP shown in this study were not statistically significant (p>0.05). Conclusion The ECP group exhibited a higher trend of increase in Ang-1 level compared to the sham group. The Ang-2 level was slightly lowered in the ECP group, while increased in the sham group. Although it was not statistically significant, the increasing trend in the Ang-1 level may provide an additional understanding of the ECP angiogenic effects. Therefore, further studies to validate these results are warranted.

DLP-printed GelMA-PMAA scaffold for bone regeneration through endochondral ossification.

Intramembranous ossification (IMO) and endochondral ossification (ECO) are two pathways of bone regeneration. The regeneration of most bone, such as limb bone, trunk bone, and skull base bone, mainly occurs in the form of endochondral ossification, which has also become one of the effective ways for bone tissue engineering. In this work, we prepared a well-structured and biocompatible methacrylated gelatin/polymethacrylic acid (GelMA/PMAA) hydrogel by digital light processing (DLP) printing technology, which could effectively chelate iron ions and continuously activate the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway to promote the process of endochondral ossification and angiogenesis. The incorporation of PMAA endowed the hydrogel with remarkable viscoelasticity and high efficacy in chelation of iron ions, giving rise to the activation of HIF-1α signaling pathway, improving chondrogenic differentiation in the early stage, and facilitating vascularization in the later stage and bone remodeling. Therefore, the findings have significant implications on DLP printing technology of endochondral osteogenesis induced by the iron-chelating property of biological scaffold, which will provide an effective way in the development of novel bone regeneration.

Interaction of Some Amino-Nitrile Derivatives with Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) Using a Theoretical Model.

Some studies indicate that the angiogenesis process is related to vascular endothelial growth factor, which can interact with endothelial cell surface receptors (VEGF-R1, VEGF-R2, and VEGF-R3); this biochemical process and other factors result in the promotion and growth of new blood vessels under normal conditions. However, some studies indicate that this phenomenon could also occur in cancer cells. It is important to mention that some amino derivatives have been prepared as VEGF-R1 inhibitors; however, their interaction with VEGF-R1 is not clear, perhaps due to different experimental approaches or differences in their chemical structure. The aim of this study was to evaluate the theoretical interaction of several amino-nitrile derivatives (Compounds 1 to 38) with VEGF-R1. The theoretical interaction of amino-nitrile derivatives with VEGF-R1 was carried out using the 3hng protein as the theoretical model. In addition, cabozantinib, pazopanib, regorafenib, and sorafenib were used as controls in the DockingServer program. The results showed different amino acid residues involved in the interaction of amino-nitrile derivatives with the 3hng protein surface compared with the controls. In addition, the inhibition constant (Ki) was lower for Compounds 10 and 34 than for cabozantinib. Other results show that Ki for Compounds 9, 10, 14, 27-29 and 34-36 was lower in comparison with pazopanib, regorafenib, and sorafenib. All theoretical data suggest that amino-nitrile derivatives could produce changes in the growth of some cancer cell lines through VEGFR-1 inhibition. Therefore, these amino-nitrile derivatives could be a therapeutic alternative to treat some types of cancer.

Quinacrine inhibits cMET-mediated metastasis and angiogenesis in breast cancer stem cells.

A trans-membrane receptor tyrosine kinase, cMET, belonging to the MET proto-oncogene family, is responsible for cancer metastasis and angiogenesis. But not much is known about the role of cMET in growth and progression of cancer stem cells (CSCs). Earlier studies have shown that Quinacrine (QC), a bioactive agent, has anti-CSCs activity. Here, the role of QC in deregulation of cMET-mediated metastasis and angiogenesis has been systematically evaluated in vitro in highly metastatic breast CSCs (mBCSCs), ex vivo in patient-derived breast cancer stem cells (PDBCSCs) and in vivo in xenograft mice model systems. Cell proliferation, migration, invasion and representative metastasis markers were upregulated in cMET-overexpressed cells and QC exposure inhibited these processes in both mBCSCs and PDBCSCs. Interestingly, metastasis was significantly inhibited by QC in cMET-overexpressed cells but comparatively lesser significant alteration of the process was noted in cMET-silenced cells. Increase in vascularization (in in ovo CAM assay), and cell-cell tube formation (in HUVECs), and enhanced MMP9 and MMP2 enzymatic activities (in gelatin zymography) were noted after cMET overexpression but these processes got reversed after cMET knockdown or QC treatment in cMET-overexpressed cells. QC inhibited angiogenesis significantly in cMET-overexpressed cells, but lesser significant change was observed in cMET-silenced cells. Reduction in tumor volume and decreased expression of metastatic and angiogenic markers were also noted in xenograft mice after QC treatment. Furthermore, QC inhibited cMET activity by dephosphorylation of its tyrosine residues (Y1234 and Y1356) and downregulation of its downstream cascade. Thus, QC inhibited the cMET-mediated metastasis and angiogenesis in in vitro, in ovo, in vivo and ex vivo model systems. Ligand (HGF) binding leads to receptor dimerization and phosphorylation of tyrosine kinase domain of cMET. This activates the cMET signaling cascade. The representative downstream metastasis and angiogenesis-related proteins get upregulated and induce the metastasis and angiogenesis process. But after the QC treatment, cMET get dephosphorylated and inactivated. As a result, the downstream signaling proteins of cMET along with the other representative metastatic and angiogenic factors get downregulated. These lead to inhibition of cMET-mediated metastasis and angiogenesis. (Created with BioRender.com).

Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer.

The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.

Expression of VEGF and CD-31 in traumatic ulcer of diabetic Wistar rats after application of Citrus limon peel essential oil.

Diabetes mellitus (DM) is a metabolic disease that delays the healing process, including the interruption of the processes of angiogenesis and vasculogenesis. The etiology of most angiogenic-related diseases, such as diabetes complications, includes the presence of hypoxia caused by declined vascular endothelium growth factor (VEGF) and CD-31. d-limonene, one of the main constituents of Citrus limon, is considered to have angiogenic, antioxidant, hypoglycemic, and anti-inflammatory activities. However, the exact mechanism of this process remains unclear. This study aimed to determine the potential of C. limon as a medication for diabetic ulceration. A total of 30 Wistar rats (Rattus novergicus) induced with DM and traumatic ulcers on the lower lip mucosa were divided into six groups-three each for control and treatment groups. Control groups were treated with CMC 5% gel, and treatment groups were administered with C. limon peel essential oil gel. The expression of VEGF and CD-31 was observed on days 5, 7, and 9. Immunohistochemical examinations were performed with the monoclonal antibodies anti-VEGF and anti-CD-31. ANOVA was conducted to analyze the differences between the groups (p<0.05). An increase in VEGF and CD-31 expression in the treatment group was observed compared with that of the control group (p<0.05). Citrus limon peel essential oil gel increased VEGF and CD-31 expression during the healing process of traumatic ulcers in diabetes-afflicted Wistar rats.

Investigation of the Effects of Some Cardiovascular Drugs on Angiogenesis by Transgenic Zebrafish.

Angiogenesis contributes to the pathophysiology of cardiovascular disease (CVD). Some cardiovascular drugs used in the treatment of CVD have an effect on the process of angiogenesis. Transgenic Tg (flk1: EGFP) zebrafish embryos were used to identify the effects of some cardiovascular drugs on angiogenesis during vertebral development in vivo. Zebrafish embryos at a one-cell stage or two-cell stage were cultured with embryo medium containing cardiovascular drugs at a final solvent concentration of 0.5% (V/V) dimethyl sulfoxide (DMSO) for 24 hours in 24-well plates. We found that 6 drugs including isosorbide mononitrate, amlodipine, bisoprolol fumarate, carvedilol, irbesartan, and rosuvastatin calcium may affect angiogenesis by vascular endothelial growth factor (VEGF) signaling pathway. These new findings of some cardiovascular drugs should improve the treatment of cardiovascular diseases.

Live-cell imaging-based dynamic vascular formation assay for antivascular drug evaluation and screening

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. However, most existing methods for evaluating cell vascular formation are limited to static analysis and prone to bias due to time, field of vision, and parameter selection. Code scripts, such as AngiogenesisAnalyzer.ijm, AutomaticMeasure.ijm, and VM.R., were developed to study the dynamic angiogenesis process. This method was used to screen drugs that could affect the time, maximum value, tilt, and decline rate of cell vascular formation and angiogenesis. Animal experiments have confirmed that these drugs could inhibit the formation of blood vessels. This work provides a new perspective for the research of angiogenesis process and is helpful to the development of drugs related to angiogenesis.

Parsimonious Effect of Pentoxifylline on Angiogenesis: A Novel Pentoxifylline-Biased Adenosine G Protein-Coupled Receptor Signaling Platform.

Angiogenesis is the physiological process of developing new blood vessels to facilitate the delivery of oxygen and nutrients to meet the functional demands of growing tissues. It also plays a vital role in the development of neoplastic disorders. Pentoxifylline (PTX) is a vasoactive synthetic methyl xanthine derivative used for decades to manage chronic occlusive vascular disorders. Recently, it has been proposed that PTX might have an inhibitory effect on the angiogenesis process. Here, we reviewed the modulatory effects of PTX on angiogenesis and its potential benefits in the clinical setting. Twenty-two studies met the inclusion and exclusion criteria. While sixteen studies demonstrated that pentoxifylline had an antiangiogenic effect, four suggested it had a proangiogenic effect, and two other studies showed it did not affect angiogenesis. All studies were either in vivo animal studies or in vitro animal and human cell models. Our findings suggest that pentoxifylline may affect the angiogenic process in experimental models. However, there is insufficient evidence to establish its role as an anti-angiogenesis agent in the clinical setting. These gaps in our knowledge regarding how pentoxifylline is implicated in host-biased metabolically taxing angiogenic switch may be via its adenosine A2BAR G protein-coupled receptor (GPCR) mechanism. GPCR receptors reinforce the importance of research to understand the mechanistic action of these drugs on the body as promising metabolic candidates. The specific mechanisms and details of the effects of pentoxifylline on host metabolism and energy homeostasis remain to be elucidated.

Transcriptional Profiling of a Patient-Matched Cohort of Glioblastoma (IDH-Wildtype) for Therapeutic Target and Repurposing Drug Identification

Glioblastoma (GBM) is the most prevalent and aggressive adult brain tumor. Despite multi-modal therapies, GBM recurs, and patients have poor survival (~14 months). Resistance to therapy may originate from a subpopulation of tumor cells identified as glioma-stem cells (GSC), and new treatments are urgently needed to target these. The biology underpinning GBM recurrence was investigated using whole transcriptome profiling of patient-matched initial and recurrent GBM (recGBM). Differential expression analysis identified 147 significant probes. In total, 24 genes were validated using expression data from four public cohorts and the literature. Functional analyses revealed that transcriptional changes to recGBM were dominated by angiogenesis and immune-related processes. The role of MHC class II proteins in antigen presentation and the differentiation, proliferation, and infiltration of immune cells was enriched. These results suggest recGBM would benefit from immunotherapies. The altered gene signature was further analyzed in a connectivity mapping analysis with QUADrATiC software to identify FDA-approved repurposing drugs. Top-ranking target compounds that may be effective against GSC and GBM recurrence were rosiglitazone, nizatidine, pantoprazole, and tolmetin. Our translational bioinformatics pipeline provides an approach to identify target compounds for repurposing that may add clinical benefit in addition to standard therapies against resistant cancers such as GBM.

A novel inflammation-related signature for predicting prognosis and characterizing the tumor microenvironment in colorectal cancer.

Inflammation is a critical component of tumor progression, and it modifies the tumor microenvironment by various mechanisms. Here, we explore the effect of the inflammatory response on the tumor microenvironment in colorectal cancer (CRC). A prognostic signature consisting of inflammation-related genes (IRGs) was constructed and verified based on the inflammatory response by bioinformatics analysis. IRG risk model was identified as an independent prognostic factor in CRC, and was related to biological processes of extracellular matrix, cell adhesion and angiogenesis. The IRG risk score predicted the clinical benefit of ipilimumab. Weighted correlation network analysis identified TIMP1 as the hub gene of the inflammatory response in the IRG risk model. Coculture experiments with macrophages and CRC cells revealed that TIMP1 promoted macrophage migration, inhibited the expression of M1 markers (CD11C and CD80), and promoted the expression of M2 markers (ARG1 and CD163). TIMP1 promoted the expression of ICAM1 and CCL2 by activating the ERK1/2 signaling pathway to promote macrophage migration and M2-like polarization. These IRGs in the risk model regulated stromal and immune components in the tumor microenvironment and could serve as potential therapeutic targets in CRC. TIMP1 promoted macrophage migration and meditated macrophage M2 polarization by activating ERK1/2/CLAM1 and CCL2.

Aloe vera extract wound healing sheet and free-range chicken egg albumin (gallus domesticus) accelerate angiogenesis on gingival incision wound in rats

ABSTRACTIntroduction: Incision wounds are injuries caused by dental surgery procedures. Suturing is the gold standard for post-incision management, but it can cause patient discomfort. Tissue glue can be used for wound healing, but its carcinogenicity still needs to be investigated. A Wound Healing Sheet (WHS) made of Aloe vera extract and free-range chicken egg albumin is expected to be an alternative material. Angiogenesis is a highly observable part of wound healing, as newly formed blood vessels support nutrition, act as a scaffold for cells to migrate to the wound area, and play an essential role in wound healing. This study aimed to analyze the effect of WHS made from Aloe vera extract and free-range chicken egg albumin (Gallus domesticus) on the number of vascular that show the acceleration of healing in gingival incision wounds. Methods: Quasi experimental study with a total sample of 24 male rats (Rattus norvegicus Wistar strain) with gingival incision were divided into four groups, namely T1 (50% WHS treated group), T2 (100% WHS treated group, S (suturing treated group as positive control), and NC (negative control, without treatment). The treatment was performed throughout seven days. The data obtained were analyzed statistically using One-way ANOVA and Post Hoc LSD. Results: The highest vascular count was in the T2 Group (8+1.63); followed by T1 (7+1.60); S (7+ 1.49); and NC (4+1.41). Statistical analysis showed that there was a significant difference between groups S, T1, T2 with NC (p-value &lt; 0.05); interestingly, there was no significant difference between S, T1, T2 (p-value &gt; 0.05). Conclusion: Wound Healing Sheet made of Aloe vera extract and free-range chicken egg albumin (Gallus domesticus) can accelerate the angiogenesis process on gingival incision wound in rats.Keywords: wound healing, aloe vera, gallus domesticus, egg white, angiogenesis

Immunological and immunohistochemical features of endometrial implantation factor in healthy patients of late reproductive age

Аbstract. Relevance. The number of women of older reproductive age is steadily increasing, and repeated failures of Assisted Reproductive Technologies programs during the transfer of high-quality embryos indicate the possibility of disruption of embryo implantation processes associated with impaired receptivity and functionality of the endometrium. Morphological, immunological and immunohistochemical changes in the endometrium associated with age factor may be decisive for the formation of the «implantation window» and correction of these changes and may improve the outcomes of Assisted Reproductive Technologies for a cohort of patients of older reproductive age. The aim of the study - to expand the pathogenetic understanding of the violation of the implantation ability of the endometrium in healthy patients of older reproductive age. Materials and Methods. A prospective sample study of 46 patients (group 1), aged 38 to 45 years with an officially registered diagnosis of infertility lasting no more than 4 years, with a successful gynecological and obstetric history, who were about to have their first IVF attempt, was conducted. The patients were examined according to Order № 803n of the Ministry of Health of the Russian Federation. Additionally, the level of peripheral blood melatonin, the determination of progesterone, estrogen, HLA-DR (MHC II), CD56 (NK cells), CD138, leukemia inhibiting factor receptors in the endometrium were studied. Concentrations of IL-6, IL-10, TGFß, and VGEF were determined in the cervical secretion, with the calculation of the pro-inflammatory index, as the ratio of IL-6/IL-10 cu and the ratio of TGFß1/VEGF. Statistical data processing was performed using the Statistica 10.0 application software package (StatSoft, Inc., USA). Results and Discussion. In the group of healthy patients of older reproductive age, there is an imbalance of steroid receptors and secretory transformation of the endometrium against the background of relative hyperestrogenism, with a decrease in the reception of own hormones in the endometrium. A decrease in melatonin signals a disorder of pineal and pituitary control over ovarian cycling. There is a decrease in the expression of leukemia inhibiting factor. Signs of inactive chronic endometritis with an autoimmune component are monitored, confirmed by a pro-inflammatory cytokine balance. The predominance of fibrosis processes over angiogenesis processes is confirmed by an increase in the ratio of TGFß1/VEGF and highly resistant blood flow in the uterine arteries. Conclusion. Standard pre-gravidar preparation cannot compensate for all factors that violate the implantation potential of the endometrium in this cohort of patients and requires the development of new complex techniques that directly affect the diversity of all factors that ensure the natural extinction of reproductive potential in order to increase the effectiveness of Assisted Reproductive Technologies programs.

Regulatory roles of copper metabolism and cuproptosis in human cancers.

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

Platelets at the Vessel Wall in Non-Thrombotic Disease.

Platelets are small, anucleate entities that bud from megakaryocytes in the bone marrow. Among circulating cells, platelets are the most abundant cell, traditionally involved in regulating the balance between thrombosis (the terminal event of platelet activation) and hemostasis (a protective response to tissue injury). Although platelets lack the precise cellular control offered by nucleate cells, they are in fact very dynamic cells, enriched in preformed RNA that allows them the capability of de novo protein synthesis which alters the platelet phenotype and responses in physiological and pathological events. Antiplatelet medications have significantly reduced the morbidity and mortality for patients afflicted with thrombotic diseases, including stroke and myocardial infarction. However, it has become apparent in the last few years that platelets play a critical role beyond thrombosis and hemostasis. For example, platelet-derived proteins by constitutive and regulated exocytosis can be found in the plasma and may educate distant tissue including blood vessels. First, platelets are enriched in inflammatory and anti-inflammatory molecules that may regulate vascular remodeling. Second, platelet-derived microparticles released into the circulation can be acquired by vascular endothelial cells through the process of endocytosis. Third, platelets are highly enriched in mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels. Lastly, platelets are enriched in proteins and phosphoproteins which can be secreted independent of stimulation by surface receptor agonists in conditions of disturbed blood flow. This so-called biomechanical platelet activation occurs in regions of pathologically narrowed (atherosclerotic) or dilated (aneurysmal) vessels. Emerging evidence suggests platelets may regulate the process of angiogenesis and blood flow to tumors as well as education of distant organs for the purposes of allograft health following transplantation. This review will illustrate the potential of platelets to remodel blood vessels in various diseases with a focus on the aforementioned mechanisms.