MiRNAs as new potential biomarkers and therapeutic targets in brain metastasis.

Brain metastases represent a formidable challenge in cancer management, impacting a significant number of patients and contributing significantly to cancer-related mortality. Conventional diagnostic methods frequently fall short, underscoring the imperative for non-invasive alternatives. Non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), present promising avenues for exploration. These ncRNAs exert influence over the prognosis and treatment resistance of brain metastases, offering valuable insights into underlying mechanisms and potential therapeutic targets. Dysregulated ncRNAs have been identified in brain metastases originating from various primary cancers, unveiling opportunities for intervention and prevention. The analysis of ncRNA expression in bodily fluids, such as serum and cerebrospinal fluid, provides a noninvasive means to differentiate brain metastases from primary tumors. NcRNAs, particularly miRNAs, assume a pivotal role in orchestrating the immune response within the brain microenvironment. MiRNAs exhibit promise in diagnosing brain metastases, effectively distinguishing between normal and cancer cells, and pinpointing the tissue of origin for metastatic brain tumors. The manipulation of miRNAs holds substantial potential in cancer treatment, offering the prospect of reducing toxicity and enhancing efficacy. Given the limited treatment options and the formidable threat of brain metastases in cancer patients, non-coding RNAs, especially miRNAs, emerge as beacons of hope, serving as both diagnostic tools and therapeutic targets. Further clinical studies are imperative to validate the specificity and sensitivity of ncRNAs, potentially reshaping approaches to tackle this challenge and elevate treatment outcomes for affected patients.

Methods of miRNA delivery and possibilities of their application in neuro-oncology.

In the current phase of medical progress, practical neuro-oncology faces critical challenges. These include the quest for and development of innovative methodological approaches, as well as the enhancement of conventional therapies to boost their efficacy in treating brain tumors, especially the malignant varieties. Recent strides in molecular and cellular biology, molecular genetics, and immunology have charted the primary research pathways in the development of new anti-cancer medications, with a particular focus on microRNA (miRNA)-based therapy. MiRNAs possess the ability to function as suppressors of tumor growth while also having the potential to act as oncogenes. MiRNAs wield control over numerous processes within the human body, encompassing tumor growth, proliferation, invasion, metastasis, apoptosis, angiogenesis, and immune responses. A significant impediment to enhancing the efficacy of brain tumor treatment lies in the unresolved challenge of traversing the blood-brain barrier (BBB) and blood-tumor barrier (BTB) to deliver therapeutic agents directly to the tumor tissue. Presently, there is a worldwide effort to conduct intricate research and design endeavors aimed at creating miRNA-based dosage forms and delivery systems that can effectively target various structures within the central nervous system (CNS). MiRNA-based therapy stands out as one of the most promising domains in neuro-oncology. Hence, the development of efficient and safe methods for delivering miRNA agents to the specific target cells within brain tumors is of paramount importance. In this study, we will delve into recent findings regarding various methods for delivering miRNA agents to brain tumor cells. We will explore the advantages and disadvantages of different delivery systems and consider some clinical aspects of miRNA-based therapy for brain tumors.

The function of miRNAs in the process of kidney development.

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that typically consist of 19-25 nucleotides in length. These molecules function as essential regulators of gene expression by selectively binding to complementary target sequences within messenger RNA (mRNA) molecules, consequently exerting a negative impact on gene expression at the post-transcriptional level. By modulating the stability and translation efficiency of target mRNAs, miRNAs play pivotal roles in diverse biological processes, including the intricate orchestration of organ development. Among these processes, the development of the kidney has emerged as a key area of interest regarding miRNA function. Intriguingly, recent investigations have uncovered a subset of miRNAs that exhibit remarkably high expression levels in the kidney, signifying their close association with kidney development and diseases affecting this vital organ. This growing body of evidence strongly suggests that miRNAs serve as crucial regulators, actively shaping both the physiological processes governing kidney function and the pathological events leading to renal disorders. This comprehensive review aims to provide an up-to-date overview of the latest research progress regarding miRNAs and their involvement in kidney development. By examining the intricate interplay between miRNAs and the molecular pathways driving kidney development, this review seeks to elucidate the underlying mechanisms through which miRNAs exert their regulatory functions. Furthermore, an in-depth exploration of the role played by miRNAs in the occurrence and progression of renal dysplasia will be presented. Renal dysplasia represents a significant developmental anomaly characterized by abnormal kidney tissue formation, and miRNAs have emerged as key players in this pathological process. By shedding light on the intricate network of miRNA-mediated regulatory mechanisms involved in kidney dysplasia, this review aims to provide valuable insights for the diagnosis and research of diseases associated with aberrant kidney development.

Cell-Free miRNAs as Non-Invasive Biomarkers in Brain Tumors.

Diagnosing brain tumors, especially malignant variants, such as glioblastoma, medulloblastoma, or brain metastasis, presents a considerable obstacle, while current treatment methods often yield unsatisfactory results. The monitoring of individuals with brain neoplasms becomes burdensome due to the intricate tumor nature and associated risks of tissue biopsies, compounded by the restricted accuracy and sensitivity of presently available non-invasive diagnostic techniques. The uncertainties surrounding diagnosis and the tumor's reaction to treatment can lead to delays in critical determinations that profoundly influence the prognosis of the disease. Consequently, there exists a pressing necessity to formulate and validate dependable, minimally invasive biomarkers that can effectively diagnose and predict brain tumors. Cell-free microRNAs (miRNAs), which remain stable and detectable in human bodily fluids, such as blood and cerebrospinal fluid (CSF), have emerged as potential indicators for a range of ailments, brain tumors included. Numerous investigations have showcased the viability of profiling cell-free miRNA expression in both CSF and blood samples obtained from patients with brain tumors. Distinct miRNAs demonstrate varying expression patterns within CSF and blood. While cell-free microRNAs in the blood exhibit potential in diagnosing, prognosticating, and monitoring treatment across diverse tumor types, they fall short in effectively diagnosing brain tumors. Conversely, the cell-free miRNA profile within CSF demonstrates high potential in delivering precise and specific evaluations of brain tumors.

The role and clinical relevance of long non-coding RNAs in glioma.

Glioma represents a complex and heterogeneous disease, posing significant challenges to both clinicians and researchers. Despite notable advancements in glioma treatment, the overall survival rate for most glioma patients remains dishearteningly low. Hence, there is an urgent necessity to discover novel biomarkers and therapeutic targets specifically tailored for glioma. In recent years, long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression and have garnered attention for their involvement in the development and progression of various cancers, including glioma. The dysregulation of lncRNAs plays a critical role in glioma pathogenesis and influences clinical outcomes. Consequently, there is growing interest in exploring the potential of lncRNAs as diagnostic and prognostic biomarkers, as well as therapeutic targets. By understanding the functions and dysregulation of lncRNAs in glioma, researchers aim to unlock new avenues for the development of innovative treatment strategies catered to glioma patients. The identification and thorough characterization of lncRNAs hold the promise of novel therapeutic approaches that could potentially improve patient outcomes and enhance the management of glioma, ultimately striving for better prospects and enhanced quality of life for those affected by this challenging disease. The primary objective of this paper is to comprehensively review the current state of knowledge regarding lncRNA biology and their intricate roles in glioma. It also delves into the potential of lncRNAs as valuable diagnostic and prognostic indicators and explores their feasibility as promising targets for therapeutic interventions.

MiRNAs and lncRNAs in the regulation of innate immune signaling.

The detection and defense against foreign agents and pathogens by the innate immune system is a crucial mechanism in the body. A comprehensive understanding of the signaling mechanisms involved in innate immunity is essential for developing effective diagnostic tools and therapies for infectious diseases. Innate immune response is a complex process involving recognition of pathogens through receptors, activation of signaling pathways, and cytokine production, which are all crucial for deploying appropriate countermeasures. Non-coding RNAs (ncRNAs) are vital regulators of the immune response during infections, mediating the body's defense mechanisms. However, an overactive immune response can lead to tissue damage, and maintaining immune homeostasis is a complex process in which ncRNAs play a significant role. Recent studies have identified microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as key players in controlling gene expression in innate immune pathways, thereby participating in antiviral defenses, tumor immunity, and autoimmune diseases. MiRNAs act by regulating host defense mechanisms against viruses, bacteria, and fungi by targeting mRNA at the post-transcriptional level, while lncRNAs function as competing RNAs, blocking the binding of miRNAs to mRNA. This review provides an overview of the regulatory role of miRNAs and lncRNAs in innate immunity and its mechanisms, as well as highlights potential future research directions, including the expression and maturation of new ncRNAs and the conservation of ncRNAs in evolution.

The Effect of Whole Blood and Bone Marrow with the Addition of Pyrimidine-2,4(1h,3h)-dione Thietanyl Derivatives on Free Radical Oxidation.

BACKGROUND: It is relevant to study the general patterns and identify non-specific mechanisms of body protective and adaptive reactions violation, which can lead to the various pathological processes and develop principles for the correction of these disorders. One of the therapy and prevention directions is the search for new medicines. In recent years, new derivatives of pyrimidine bases have been synthesized and studied. Pyrimidine-based medicines have a membrane-stabilizing and immunomodulatory effect and can normalize metabolic disorders and increase the oxidative activity of leukocytes. Disruption of the free radical oxidation processes, the generation of reactive oxygen species and lipid peroxidation, including in whole blood and bone marrow, has gained importance in recent years. METHODS: Each reaction was monitored by thin layer chromatography. 1H, 13C, and 15N NMR spectra were recorded (chemical shifts were expressed as δ-values). We studied the effect of 6-methyl-3-(thietan- 3-yl)pyrimidine-2,4(1H,3H)-dione on the generation of reactive oxygen species (ROS) in the whole blood and bone marrow using the study of whole blood spontaneous and stimulated chemiluminescence (CL). CL methods make it possible to quickly and easily assess the studied material (whole blood, bone marrow) effect on free radical oxidation. Using CL methods, it is possible to reveal the presence of medicines' pro- or antioxidant properties, opening up new possibilities in the search for substances with antioxidant properties and comparing their activity. RESULTS: Alkylation of 6-methylpyrimidine-2,4(1H,3H)-dione by 2-chloromethylthiirane in protic solvents in the presence of alkali leads to the formation of an N-thietane derivative. NMR spectroscopy showed that 6-methylpyrimidine-2,4(1H,3H)-dione was alkylated at position 3. The oxidation reactions of N-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione were studied, and it was determined that, depending on the excess of the oxidizing agent and the duration of the process, N-(1-oxothietan-3-yl)- or N-(1,1-- dioxothietan-3-yl)pyrimidine-2,4(1H,3H)-diones were formed. The effects of free radical oxidation processes of new biologically active pyrimidine-2,4(1H,3H)-diones were studied. CONCLUSION: New pyrimidine-2,4(1H,3H)-diones increase the general adaptive capabilities of the body and have protective effects in extreme conditions.

Phase I/II trial of local interstitial chemotherapy with arsenic trioxide in patients with newly diagnosed glioma.

Background: Glioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and adjuvant radiotherapy and chemotherapy. Arsenic trioxide could inhibit various tumors. However, it is a challenge to evaluate the efficiency and safety of srsenic trioxide in glioma patients. Objective: The arsenic trioxide has the potent therapeutic effect on glioma. However, the safety and efficacy of local interstitial chemotherapy with arsenic trioxide in newly diagnosed glioma patients is unclear. Methods: All patients received partial or complete tumor resection and intraoperative implantation of Ommaya reservoirs followed by standard radiotherapy. Arsenic trioxide with the starting dose 0.3 mg was administered via an Ommaya reservoir catheter inserted into the tumor cavity for 5 consecutive days every 3 months for a total of eight cycles unless tumor progression or excessive toxicity was observed. Results: No hematological or grade 4 non-hematological toxicity was observed in any patient during arsenic trioxide treatment. The maximum tolerated dose of 1.5 mg of arsenic trioxide was safe and well tolerated. The median overall survival for WHO grade 3 glioma was 33.6 months, and for glioblastoma was 13.9 months. The median progression-free survival for WHO grade 2 glioma was 40.3 months, for grade 3 glioma was 21.5 months, and for glioblastoma was 9.5 months. Conclusion: These results suggest that arsenic trioxide is safe and well tolerated with local delivery into the tumor cavity of the brain, and the dose recommended for a phase II trial is 1.5 mg.

Therapeutic effect of natural polyphenols against glioblastoma.

Glioblastoma (GBM) is the most common and aggressive tumor of the central nervous system, which has a highly invasive growth pattern, which creates poor prospects for patient survival. Chemotherapy and tumor surgery are limited by anticancer drug resistance and tumor invasion. Evidence suggests that combinations of treatments may be more effective than single drugs alone. Natural polyphenolic compounds have potential as drugs for the treatment of glioblastoma and are considered as potential anticancer drugs. Although these beneficial effects are promising, the efficacy of natural polyphenolic compounds in GBM is limited by their bioavailability and blood-brain barrier permeability. Many of them have a significant effect on reducing the progression of glioblastoma through mechanisms such as reduced migration and cell invasion or chemosensitization. Various chemical formulations have been proposed to improve their pharmacological properties. This review summarizes natural polyphenolic compounds and their physiological effects in glioblastoma models by modulating signaling pathways involved in angiogenesis, apoptosis, chemoresistance, and cell invasion. Polyphenolic compounds are emerging as promising agents for combating the progression of glioblastoma. However, clinical trials are still needed to confirm the properties of these compounds in vitro and in vivo.

MicroRNAs-mediated regulation of glucose transporter (GLUT) expression in glioblastoma.

Current knowledge about the role of microRNAs (miRNAs) in tumor glucose metabolism is growing, and a number of studies regularly confirm the impact miRNAs can have on glucose metabolism reprogramming in tumors. However, there remains a lack of understanding of the broader perspective on the role of miRNAs in energy reprogramming in glioblastoma. An important role in the metabolism of glucose is played by carrier proteins that ensure its transmembrane movement. Carrier proteins in mammalian cells are glucose transporters (GLUTs). In total, 12 types of GLUTs are distinguished, differing in localization, affinity for glucose and ability to regulate. The fact of increased consumption of glucose in tumors compared to non-proliferating normal tissues is known. Tumor cells need glucose to ensure their survival and growth, so the type of transport proteins like GLUT are critical for them. Previous studies have shown that GLUT-1 and GLUT-3 may play an important role in the development of some types of malignant tumors, including glioblastoma. In addition, there is evidence of how GLUT-1 and GLUT-3 expression is regulated by miRNAs in glioblastoma. Thus, the aim of this study is to highlight the role of specific miRNAs in modulating GLUT levels in order to take into account the use of miRNAs expression modulators as a useful strategy to increase the sensitivity of glioblastoma to current therapies.

Modern aspects of the use of natural polyphenols in tumor prevention and therapy.

Polyphenols are secondary plant metabolites or organic compounds synthesized by them. In other words, these are molecules that are found in plants. Due to the wide variety of polyphenols and the plants in which they are found, these compounds are divided according to the source of origin, the function of the polyphenols, and their chemical structure; where the main ones are flavonoids. All the beneficial properties of polyphenols have not yet been studied, since this group of substances is very extensive and diverse. However, most polyphenols are known to be powerful antioxidants and have anti-inflammatory effects. Polyphenols help fight cell damage caused by free radicals and immune system components. In particular, polyphenols are credited with a preventive effect that helps protect the body from certain forms of cancer. The onset and progression of tumors may be related directly to oxidative stress, or inflammation. These processes can increase the amount of DNA damage and lead to loss of control over cell division. A number of studies have shown that oxidative stress uncontrolled by antioxidants or an uncontrolled and prolonged inflammatory process increases the risk of developing sarcoma, melanoma, and breast, lung, liver, and prostate cancer. Therefore, a more in-depth study of the effect of polyphenolic compounds on certain signaling pathways that determine the complex cascade of oncogenesis is a promising direction in the search for new methods for the prevention and treatment of tumors.

Functions of the bone morphogenetic protein signaling pathway through non-coding RNAs.

Bone morphogenetic proteins (BMPs) are proteins of the transforming growth factor-ß (TGF-ß) family, which plays an important role in the formation of skeletal and cartilage tissue and their regeneration. BMPs play a key role in the formation of new blood vessels and promote the migration, proliferation, and differentiation of mesenchymal stem cells (MSCs) into chondroblasts and osteoblasts. It is known that malfunction of BMPs signaling can cause a disease state. Epigenetic regulation of expression plays a key role in the control of many cellular processes. Important participants in this regulation are non-coding RNAs (ncRNAs), which are RNA molecules that are not translated into proteins. The best known of these are microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). In addition, the results of many studies make it possible to establish an unambiguous functional relationship between these ncRNAs. Being involved in the regulation of a large number of target genes responsible for the life of the cell, miRNAs, lncRNAs, and circRNAs are essential for the normal development and functioning of the body, and the violation of their functions accompanies the development of many pathophysiological processes including oncogenesis. In the present review, we discuss different insights into the regulation of BMPs signaling pathway by miRNAs, lncRNAs and circRNAs governed.

Endovascular Treatment of Acute Ischemic Stroke Due to Isolated Proximal Posterior Artery Occlusion.

Background: Acute ischemic stroke (AIS) due to isolated proximal posterior cerebral artery (PPCA) occlusion is rare but associated with high morbidity and mortality rates. However, the optimal treatment strategy for patients with AIS caused by PPCA remains unclear. We discuss our single-center experience with endovascular treatment (EVT) in patients with PPCA. Methods: Data from patients with AIS due to PPCA occlusion were retrospectively analyzed. We analyzed procedural details, the degree of reperfusion, functional outcomes, and complications. Functional outcomes were determined using the modified Rankin Scale (mRS) at 90 days, and good outcome was defined as mRS 0-2 at 90 days. Successful reperfusion was defined as modified treatment in cerebral ischemia (mTICI) 2b-3 after endovascular therapy. Safety variables included symptomatic hemorrhage (defined as an increase of four or more points in the National Institute of Health Stroke Scale score), vessel perforation or dissection, and new ischemic stroke in different territories. Results: Seven patients were included in this study. The mean age of the patients was 64 ± 12.4 years. Successful reperfusion was achieved in all seven patients (100%). Good outcomes were achieved at 90 days in 2 patients (28.6%), and favorable outcomes were observed in five patients (71.4%). One patient underwent angioplasty as rescue therapy after three attempts. One patient died because of severe gastrointestinal bleeding 24 h after EVT, which was probably a complication of intravenous alteplase. One patient had an embolism in the basilar artery and achieved complete reperfusion after rescue thrombectomy. Another patient had a complication of vessel dissection in the PPCA and underwent stent implantation as rescue therapy. We observed no recurrence of ischemic stroke or any intracranial hemorrhage on non-contrast computed tomography 24 h after the procedure. Conclusion: EVT may represent an alternative treatment strategy for patients with acute ischemic stroke caused by PPCA.

Diagnostic Investigations as a Basis for Optimising Surgical Management of Vertebrobasilar Insufficiency Syndrome.

Vertebrobasilar insufficiency (VBI) is one of the most common forms of cerebrovascular pathology. The progression of the VBI, especially in the context of inadequate therapy, often leads to the formation of a persistent neurological deficits within the framework of dyscirculatory encephalopathy and the consequences of a stroke in the vertebrobasilar system. This study demonstrate the importance of objective methods of patient investigation to optimize the choice of the most effective methods of surgical treatment for VBI in cases of ineffective medical treatment. We have shown that the optimization of the diagnostic algorithm contributes to the correct individualized determination of types of surgical treatment for patients with VBI. It was found that, in addition to traditional diagnostic methods, the use of radiographic methods (ultrasound Doppler, multispiral computed tomography with contrast enhancement) is invaluable for choosing the tactics of surgical treatment. We propose a significant outcome indicator like the blood flow reactivity index to determine the postoperative improvement of blood flow in the vertebral arteries. In addition, the need to perform cerebral angiography and consultations with related specialists to exclude pathologies with a similar clinical picture is emphasized.

Application of Intraoperative Ultrasound Navigation in Neurosurgery.

Effective intraoperative image navigation techniques are necessary in modern neurosurgery. In the last decade, intraoperative ultrasonography (iUS), a relatively inexpensive procedure, has gained widespread acceptance. Aim: To document and describe the neurosurgery cases, in which iUS has been employed as the primary navigational tool. This includes a discussion of the advantages that iUS may possess relative to other forms of neuronavigation. Conclusion: The application of iUS as an intraoperative navigation tool during neurosurgery holds great potential as it has been shown, relative to other neuronavigation techniques, to be quick, repeatable, and able to provide real-time results.

Comparing Two Improved Techniques With the Traditional Surgical Techniques for Intra and Extramedullary Spinal Tumor Resection: A Report of 280 Cases.

Objectives: Spinal tumors remain a challenging problem in modern neurosurgery. The high rate of postoperative morbidity associated with intramedullary tumors makes the need for safer surgical techniques invaluable. This study analyses our experience with the treatment of spinal cord tumors and compares traditional management and a new different surgical approach to intramedullary tumors with an associated hydrosyringomyelia. Materials and Methods: This retrospective study compared standard surgical techniques and 2 newer modified techniques for intra and extramedullary spinal tumors at the Neurosurgery center for spinal cord tumors of the Republic of Uzbekistan. Preoperative neurological status was recorded with the ASIA/ISNCSCI scale. Postoperative outcome was graded using the Nurrick score. Results: Of the 280 cases, there were 220 (78.5%) extramedullary and 60 (21.5%) with intramedullary spinal tumors. The control and main group had 159 (56.8%) and 121 (43.2%) patients, respectively. Severe compression myelopathy (ASIA- A, B, C) was 217 (77.5%) patients i.e., ASIA A-39 (13.9%); B-74 (26.4%), and C-104 (37.1%). In 74 extramedullary tumors (33.6%) treated with the new method, good postoperative outcomes in 44 cases (59.5%) with OR = 1.9; 95% CI 1.1-3.3 (p < 0.05). Thirty-seven (61.7%) intramedullary tumors were treated with the newer modified technique. There was no difference with the standard method (p = 0.15). However, when comparing postoperative Nurick grade 1-2 with grade 3-4, the newer strategy was superior with improvement in 24 (65%) patients, OR = 3.46; 95% CI 1.2-10.3 (p < 0.05). Conclusion: When compared with standard methods, the proposed newer modified strategy of surgical treatment of spinal cord tumors with the insertion of a syringosubarachnoid shunt in the presence of an associated hydrosyringomyelia is associated with better postoperative outcome (Nurick 1 and 2) in 64.8%.

Synthesis of new 1,3-thiazol derivatives of maleopimaric acid as anticancer, antibacterial and antifungal agents.

A series of new 1,3-thiazole derivatives of maleopimaric acid 6a-f, 7a-f were synthesized and evaluated for anticancer, antibacterial and antifungal activities. Evaluation of cytotoxic activity against human embryonic kidney 293 cells (HEK293), human neuroblastoma cell line (SH-SY5Y), hepatocellular carcinoma cell line (HepG2) and human T-cell lymphoblast-like line (Jurkat), showed that introduction of the aminothiazole fragment at position 6 of the diterpenoid molecule leads to decrease of cell viability. Substance 3 was found to be the most active against all tested cell lines, inhibiting cell viability with IC50 values in the range of 2-24 µM. The structure-activity relationship of these compounds was studied and the results show that the compounds 6c and 7e exhibited in vitro antifungal activity against Candida albicans and also possessed antibacterial profile against Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Proteus vulgaris.