Stage IV glioblastoma is the most frequently diagnosed and the worst prognosis tumor of the central nervous system (CNS). Patients suffering from this type of cancer usually survive several months with the use of surgica...Stage IV glioblastoma is the most frequently diagnosed and the worst prognosis tumor of the central nervous system (CNS). Patients suffering from this type of cancer usually survive several months with the use of surgical treatment, radiotherapy and chemotherapy. The development of glioblastoma is determined by a number of mutations, the most common of which are the p16, p19, p53, pRB, PTEN, PDGFR, CDK4 and EGFR protein genes as well as the loss of heterozygosity on chromosomes 10, 17 and 19. The occurrence of mutations within the IDH1 and IDH2 genes and increased methylation of MGMT promoter improves patient survival, but few patients live more than 3 years after diagnosis. The most important cell signaling pathways in glioblastoma are PI3K/Akt/mTOR and Wnt/β-catenin, which play a key role in tumor cell function. However, these cells are highly resistant to anticancer drugs, including inhibitors of cell signaling pathways. Currently, the potential methods of effectively combating malignant gliomas are alternating electric field therapy and the implementation of new immunotherapeutic strategies.
Cancer, type 2 diabetes, cardiovascular and neurological diseases are disorders commonly classified as diseases that have a significant impact on the length and quality of human life. Sirtuins play an important role in t...Cancer, type 2 diabetes, cardiovascular and neurological diseases are disorders commonly classified as diseases that have a significant impact on the length and quality of human life. Sirtuins play an important role in their pathogenesis and complications. Numerous studies indicate that modulation of the expression of these proteins can slow down the processes of aging and cell death, prevent inflammation, and regulate metabolic processes, and consequently modify the progression of the disease. One of the best-known sirtuins is sirtuin 1, whose strongest natural activator is resveratrol. The development of alternative therapies involving natural compounds such as resveratrol is highly desirable due to the significantly lower number of side effects compared to conventional therapies. Therefore, this review summarizes the possible benefits of resveratrol as a sirtuin 1 activator in the prevention and treatment of human diseases based on the results of the studies conducted so far.
CD14 is one of the key proteins involved in the activation of the inflammatory response of immune cells. CD14 binds bacterial lipopolysaccharide (LPS) and transfers its molecules to the complex of Toll-like receptor 4 (T...CD14 is one of the key proteins involved in the activation of the inflammatory response of immune cells. CD14 binds bacterial lipopolysaccharide (LPS) and transfers its molecules to the complex of Toll-like receptor 4 (TLR4) and MD-2 protein, which in turn triggers pro-inflammatory signaling pathways necessary to combat infection. CD14 determines the final shape of the pro-inflammatory reaction of cells to LPS, serving as a transporter of this endotoxin and also as a regulator of TLR4 activity. In addition, CD14 transports other molecules of microbial or endogenous origin to their target receptors/proteins, participating in the activation of pro-inflammatory signaling pathways triggered by the presence of pathogens, as well as tissue damage. Currently, more attention is paid to the role of the CD14 protein in the development of non-infectious diseases such as autoimmune diseases, metabolic diseases and cardiovascular diseases.
The skin, as the largest organ of the body, is constantly exposed to environmental threats, including: injuries and oxidative stress. The thioredoxin system is one of the skin antioxidant systems , which protects cells a...The skin, as the largest organ of the body, is constantly exposed to environmental threats, including: injuries and oxidative stress. The thioredoxin system is one of the skin antioxidant systems , which protects cells against oxidative stress, regulates cell migration, proliferation and apoptosis, and also participates in signal transmission by regulating the activity of transcription factors. Recent studies have shown a correlation between the epidermal transcription factor Foxn1 and the thioredoxin system in mouse skin. Mass spectrometry analysis, followed by in vitro and in vivo experiments, showed that Foxn1 in keratinocytes regulates elements of the electron transport chain as well as the thioredoxin system (Txn2, Txnrd3), especially under hypoxic condition. High levels of Txnrd3 mRNA were detected for the first time in the injured skin of Foxn1+/+ mice compared to Foxn1-/- mice, and also showed that Foxn1 in keratinocytes upregulates Txnrd3 protein expression. Moreover, in silico analyzes indicated possible binding sites of the transcription factor Foxn1 in the Txn system. In conclusion, the data presented in this review identify Foxn1 as a novel component of the skin antioxidant system.
The problem of regeneration of damaged peripheral nerves is an ongoing topic and has long been the subject of intensive research worldwide. This study examined the morphological and functional evaluation of the regenerat...The problem of regeneration of damaged peripheral nerves is an ongoing topic and has long been the subject of intensive research worldwide. This study examined the morphological and functional evaluation of the regeneration process within the damaged sciatic nerve, a mouse animal model. The effect of impaired expression of the TSC-1 gene on the process of nerve regeneration was evaluated, depending on the mode of damage. The research object consisted of 48, 2-month-old male TSC lines. The test group consisted of animals that underwent damage to the sciatic nerve by crushing, freezing and electrocoagulation, while the control group includes mice whose sciatic nerve was not damaged. Behavioral tests were conducted to evaluate the functional return of the limb, after 3,5,7 and 14 days. The first changes in the regeneration process of the damaged neurite are observed as early as day 3 after the injury, while on day 14 after the injury the functional return of the damaged limb was noted.
The main function of bile acids (BA) is participation in the emulsification of dietary fats. Recently it has been discovered that BAs can also act as signaling molecules regulating the processes of their own synthesis an...The main function of bile acids (BA) is participation in the emulsification of dietary fats. Recently it has been discovered that BAs can also act as signaling molecules regulating the processes of their own synthesis and metabolism, as well as glucose and lipid metabolism. In addition, they affect the motility of the digestive tract and food intake. BA also interacts with the gut microbiota, a major player in their metabolism. Most of the regulatory actions of BAs are mediated by their receptors, the most important of which are the farnesoid X receptor (FXR) and the G protein-coupled receptor -TGR5, found in large amounts in the intestine, liver, adipose tissue and other tissues of the body. Recently, much attention has been paid to the influence of BA on various diseases and the possibility of using them in the treatment of e.g. inflammatory bowel disease, liver diseases, type 2 diabetes and obesity.
Damage to the musculoskeletal system significantly impairs mobility and quality of life, limiting everyday activities. For a successful orthopedic treatment, anatomical, physiological and biomechanical factors must be ta...Damage to the musculoskeletal system significantly impairs mobility and quality of life, limiting everyday activities. For a successful orthopedic treatment, anatomical, physiological and biomechanical factors must be taken into account as they all influence tissue healing. It is therefore of crucial importance to support traditional treatment with biological therapies, as they facilitate the regeneration of the tissue microarchitecture. Such orthobiologics work at the cellular level (orthobiologics rich in mesenchymal cells or growth factors) or at the tissue level (matrices for repairing e.g. cartilage). In this review, we describe the most frequently used orthobiologics rich in mesenchymal cells (bone marrow, autologous adipose tissue, tenocytes, umbilical cord, urine and bursa) and growth factors, presenting the molecular basis of their functioning and their clinical effectiveness.
Glycosylated proteins play a key role in the various stages of bacterial and viral invasions. Glycosylation is a common process across all domains of life. Initially, this process was attributed only to eukaryotic organi...Glycosylated proteins play a key role in the various stages of bacterial and viral invasions. Glycosylation is a common process across all domains of life. Initially, this process was attributed only to eukaryotic organisms, in which the synthesis takes place in the rough endoplasmic reticulum and the Golgi apparatus. Over time, it has been shown that many bacteria and viruses express N-glycans and O-glycans on their surface. Prokaryotes are able to synthesize glycans, while virions take over the host's cellular machinery to produce glycans. Pathogens use glycoproteins to regulate adhesion to infected cells (Ebola virus), protect receptor-binding epitopes (HIV) and evade the immune system detection by molecular mimicry (Helicobacter pylori, Haemophilus influenzae). Successful infection also depends on the host surface glycans, mainly in determining the tissue tropism of viruses (Influenza A viruses) and the sliding motility of bacteria (Mycoplasma sp.). Modification of glycan structures, important at various levels of the infectious cycle, creates new therapeutic possibilities that gives a chance to limit the spread of infectious diseases.
Traumatic damage to the nervous system has been a common occurrence for years, reducing patients' quality of life. The mammalian target of rapamycin (mTOR) pathway plays a key role in nervous system physiology, including...Traumatic damage to the nervous system has been a common occurrence for years, reducing patients' quality of life. The mammalian target of rapamycin (mTOR) pathway plays a key role in nervous system physiology, including by controlling nerve cell survival and differentiation. Excessive activation of the mTOR pathway leads to an increase in cell cycle protein activity and apoptosis of nerve cells. Moreover, current findings suggest the involvement of the mTOR pathway in neuroplasticity. The use of transgenic animals with deletion of the TSC gene as well as various models of sciatic nerve damage, allows activation of the mTOR pathway. Currently, the results confirm that inactivation of point mutations in TSC-1 or TSC-2 genes, activates the canonical signaling pathway of the mTORC-1 complex, in turn, reactivation of the mTORC-1 pathway through the absence of the TSC-1 gene in mature neurons induces axonal regeneration. Dysfunction of the mTORC-1 pathway in Schwann cells (SC) inhibits myelination of nerve fibers. The aim of the present study is to understand the physiology and role of the mTOR pathway as well as to demonstrate the impact of TSC gene deletion in the regeneration of the nervous system. Current research on the activity of the mTOR pathway may provide new strategies to intensify peripheral nerve regeneration.
Bacteria from Pseudomonas aeruginosa species are often found in environments such as water or soil, but are also known to be opportunistic pathogens of humans and animals. Characteristic feature of these bacteria is thei...Bacteria from Pseudomonas aeruginosa species are often found in environments such as water or soil, but are also known to be opportunistic pathogens of humans and animals. Characteristic feature of these bacteria is their high ability to survive in very different ecological niches. Such capability of adaptation to changing conditions is derived from the extended regulatory networks and the use of a rich repertoire of genome-encoded proteins, pathways and adaptive mechanisms. Transcriptional regulators are key components of gene expression regulation responding to environmental signals by turning on or off specific pathways. Studies on transcription factos using transcriptomic and genomic methods provide knowledge about the mechanisms of their action, regulated genes and processes enabling understanding complex regulatory networks controlling cell life. The aim of this work is to present the results of research on the regulation of bacterial transcription visualized on the basis of P. aeruginosa pathogen and the characteristics of the mechanism of regulation of genes involved in the virulence of this bacterium.
Metabolomics is a scientific field whose topics include qualitative and quantitative analysis of metabolites, defined as the total set of low-molecular-weight chemical compounds not exceeding 1500 Da. Along with genomics...Metabolomics is a scientific field whose topics include qualitative and quantitative analysis of metabolites, defined as the total set of low-molecular-weight chemical compounds not exceeding 1500 Da. Along with genomics, transcriptomics, and proteomics, it is categorized as a field of science, currently using state-of-the-art diagnostic tools that, in the face of modern medicine, allow a holistic approach to the patient. The presence of metabolites in the analyzed biological material, in contrast to the information contained directly in the genetic material, reflects the current physiological state of the cell, and represents an integral relationship between genotype and phenotype, which can directly contribute in the future to the knowledge of the molecular basis in specific disease entities. An additional aspect that is in favor of metabolic analysis is their decidedly smaller number compared to at least genes, transcriptomes, and proteins. Despite the development of many "omics" technologies, there is a lack of integrative and linking studies to see the full picture of cellular pathways in the future. Such linkage would improve our insight into human pathologies, leading to a revolution in preclinical and clinical research in disease diagnosis, prognosis, drug response and drug development.
Synthetic cathinones are the group of the most frequently identified so-called new psychoactive substances with a strong stimulating effect and high addictive potential. It is now believed that the use of these compounds...Synthetic cathinones are the group of the most frequently identified so-called new psychoactive substances with a strong stimulating effect and high addictive potential. It is now believed that the use of these compounds increases the risk of sporadic forms of neurodegenerative diseases. The article presents current views on the mechanisms of neurotoxicity of synthetic cathinones, including: blood-brain barrier damage, mitochondrial dysfunction, oxidative stress, neuroinflammation and hyperthermia. Further understanding of the cellular and molecular processes underlying neurotoxicity and associated clinical manifestations is essential in the development of therapeutic strategies for the prevention and treatment of neuropsychiatric disorders resulting from the intake of synthetic cathinones.
The Prime Editing method introduces the expected manipulations within a given genome with a Cas9-nicase and pegRNA structure and a reverse transcriptase, which is responsible for the synthesis of the segment, which is th...The Prime Editing method introduces the expected manipulations within a given genome with a Cas9-nicase and pegRNA structure and a reverse transcriptase, which is responsible for the synthesis of the segment, which is then incorporated into the edited strand. This technique is based on the previously discovered CRISPR/Cas9 method. It differs from CRISPR/Cas9 in the absence of double cracks within the DNA helix, which is due to its complex structure, including the presence of additional elements, i. e. the reverse transcriptase and the matrix within the pegRNA. PE is used to modify the DNA double helix. The work deals mainly with the creation and improvement as well as testing of the modern Prime Editing method. Information on the structure and functioning of the system is provided, as well as the research carried out so far with the use of PE, carried out within the genomes of cells derived from plant, animal, and human organisms, is described. The paper also contains information on the potential benefits and hopes related to the use of this innovative method.
Known for a long time, well-tested substances are still finding new applications in science, medicine and industry. This is a popular and cost-effective strategy because, when searching for new applications, effective me...Known for a long time, well-tested substances are still finding new applications in science, medicine and industry. This is a popular and cost-effective strategy because, when searching for new applications, effective methods of their large-scale production and pharmacological activity, and the results of pharmacokinetic and toxicological studies are usually already known. Tamoxifen is known mainly as a drug used in the treatment of estrogen receptor-dependent breast cancer. Despite the discovery of this effective and profitable property many years ago and the constant expansion of related applications and patents, completely new ways of using tamoxifen and its derivatives in various fields continue to appear, and the number of patents for novel applications unrelated to breast cancer remains high. The aim of this article is to illustrate drug repositioning on the example of tamoxifen and to bring the ever-developing story of discoveries related to it to a wider audience.
Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activat...Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activation of the MAPK/ERK signaling pathway, significantly contributing to the process of carcinogenesis. We discuss the drug design process on the example of a specific BRAF V600E inhibitor, vemurafenib. We begin with the most commonly used drug design methods. The second part of the article focuses on vemurafenib. We analyze the invention of this BRAF V600E inhibitor and its analogue as well as the course of three stages of clinical trials. Then we provide information about other popular drugs for malignant melanoma, i.e. dacarbazine, ipilimumab and dabrafenib, and about the advantages of therapy with the simultaneous use of two inhibitors. Finally, we briefly discuss the role of artificial intelligence in the future of drug design.
Phenylalanine ammonia lyase (PAL) is a key enzyme controlling the biosynthesis of phenolic compounds in plants. PAL catalyzes ammonia elimination from L-phenylalanine in a reaction that yields cinnamic acid, a precursor...Phenylalanine ammonia lyase (PAL) is a key enzyme controlling the biosynthesis of phenolic compounds in plants. PAL catalyzes ammonia elimination from L-phenylalanine in a reaction that yields cinnamic acid, a precursor of a large group of phenylpropanoid compounds. Phenylpropanoids and their derivatives play an important role in regulating plant resistance mechanisms under environmental stresses. By reducing the level of phenolic compounds, PAL inhibitors can induce changes in plant metabolism. This paper presents the current state of knowledge on the use of PAL inhibitors in plant biology, and draws attention to the possibilities of using PAL inhibitors in agriculture in the context of the witnessed climate changes which increase the frequency and intensity of some disasters such as droughts, floods and storms. By reducing the level of phenolic compounds, PAL inhibitors can induce changes in plant metabolism. This paper presents the current state of knowledge on the use of PAL inhibitors in plant biology, and draws attention to the possibilities of using PAL inhibitors in agriculture in the context of the witnessed climate changes.
The development of methods used in molecular biology has allowed a milestone in medical and pharmaceutical sciences. Progress has also been made in the field of pharmacognosy, which places substances of natural origin co...The development of methods used in molecular biology has allowed a milestone in medical and pharmaceutical sciences. Progress has also been made in the field of pharmacognosy, which places substances of natural origin contained in plant raw materials at the center of attention. The beneficial effects of some of them have been known for years, while scientific evidence of their health-promoting properties was lacking for a long time. This was also the case with curcumin and the long road from its isolation in pure form in 1842 to the knowledge of its chemical structure in 1910. Due to the chemical properties of the molecule, curcumin is attributed with many health-promoting properties. These affect many organ systems including the skin, visual pathway, respiratory system, circulatory system, digestive system and nervous system. One of the complications that follow nerve damage is the loss of locomotor function in the animal and the development of inflammation within it. Curcumin has anti-inflammatory properties. This is confirmed by its inhibition of nuclear factor κB, a mediator in inflammatory processes. In addition, a very important field associated with neuronal dysfunction is the aging process. This is caused, among other things, by the presence of reactive oxygen species. The neuroprotective effect of curcumin allows to reduce their concentration caused by the accumulation of mutations within the mitochondrial DNA. The beneficial effect on the nervous system is due to the penetration of curcumin across the blood-brain barrier. However, its poor solubility significantly limits the therapeutic properties resulting from curcumin supplementation. Methods are currently being developed to increase its bioavailability using nanoparticles.
VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P do...VPS10P (vacuolar protein sorting 10 protein) domain receptors consitute a family of sorting receptors which are responsible for directing their protein cargo into destined subcellular localization. Functions of VPS10P domain receptors have been well-described in neurons, where efficient sorting of proteins is crucial for cell viability. Dysfunctions in neuronal actions of VPS10P domain receptors are linked to disturbances in neuronal plasticity and development of neurodegenerative disorders. VPS10P domain receptors are also crucial for lipid metabolism, mainly through transport of lipolytic enzymes or influencing the uptake of lipoproteins by the cells. Emerging evidence suggests that VPS10P domain receptors can play important roles in immune response evoked by immune or glial cells. They are also key players in pathogenesis of cancers.