Participation of oxidative stress in selected diseases in the light of the latest research

Disturbances in the balance between the production and accumulation of reactive oxygen species and the proper functioning of antioxidant systems are the source of the phenomenon called oxidative stress. In physiological conditions in the human body, the conditions of the aforementioned balance are maintained, however, in pathological conditions related to exposure to reactive oxygen species or also in the course of diseases, cellular homeostasis may be disturbed. The role of oxidative stress in the pathogenesis and course of diseases affecting many organs has been known for many years. Atherosclerosis, arterial hypertension classified as cardiovascular diseases or neurological diseases such as Parkinson's disease and Alzheimer's disease are just some examples of diseases in which the role of oxidative stress has been known for years. The discovery of new technologies, as well as the sometimes not fully understood pathogenesis of many diseases, is the basis for further research on the impact of reactive oxygen species on pathological processes occurring during the development of the disease and phenomena occurring during treatment. At present, numerous studies and clinical experiments are being carried out, the subject of which is related to the influence of reactive oxygen species on the pathogenesis, clinical picture and treatment of various diseases. Due to the fact that neoplastic diseases are expected to become the most common cause of death, the generation of oxidative stress in neoblastic cells may, on the contrary, become the basis of therapy. The purpose of this article is to review the latest scientific reports on the role of oxidative stress in the pathogenesis and course of selected diseases, i.e. neurological diseases (including Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease), cardiovascular diseases (including atherosclerosis arteries, arterial and pulmonary hypertension), lifestyle diseases (diabetes and osteoporosis) and cancer, also in the aspect of therapy with compounds that generate oxidative stress

Malignant melanoma: epidemiology, pathogenesis, diagnostics and innovative therapeutic methods

Melanoma is the most common cause of death among people with skin cancer, and its development is most often associated with excessive exposure to ultraviolet radiation and predisposing genetic factors. Early detection of melanoma significantly reduces mortality in both the short and long term. Unfortunately, this cancer has the ability to quickly reach the malignant phase and metastasize to other organs. The typical treatment for melanoma is surgical resection, but over the last few years significant progress has also been made in the field of systemic therapies, which has led to a noticeable improvement in survival in patients with metastases. The article summarizes information about modern therapeutic methods used in patients with melanoma. Drugs belonging to BRAF kinase inhibitors: vemurafenib and dabrafenib are currently the first-line therapy for advanced melanomas with a confirmed BRAF gene mutation. Modern therapeutic strategies that have revolutionized the treatment of melanoma also include immunotherapy. By blocking inhibitory checkpoints of the immune system, it is possible to generate an anti-cancer response alone or in synergy with other types of therapy. These drugs target molecules that are pathologically overexpressed in melanoma, such as PD-1 or CTLA-4. Intralesional agents, such as oncolytic viruses, can also induce immune stimulation to destroy cancer cells. The only drug of this type registered so far for the treatment of melanoma is talimogene laherparepvec, which uses a genetically modified herpes simplex virus type 1. The possibility of individually tailored treatment to the patient is created by CAR-T therapy, which involves collecting tumor-infiltrating T lymphocytes from the patient, modifying them to obtain a receptor that specifically recognizes melanoma cells, and then multiply and introduce it into the patient's body. Recent findings have shown higher success rates with combinations of immunotherapy and chemotherapy, radiotherapy, or targeted molecular therapy. Despite the success of modern systemic therapy, many melanoma patients do not respond to treatment or develop drug resistance, which leads to the constant need to look for new solutions in the fight against this cancer

Astrogliosis in an Experimental Model of Hypovitaminosis B12: A Cellular Basis of Neurological Disorders due to Cobalamin Deficiency

Cobalamin deficiency affects human physiology with sequelae ranging from mild fatigue to severe neuropsychiatric abnormalities. The cellular and molecular aspects of the nervous system disorders associated with hypovitaminosis B12 remain largely unknown. Growing evidence indicates that astrogliosis is an underlying component of a wide range of neuropathologies. Previously, we developed an in vitro model of cobalamin deficiency in normal human astrocytes (NHA) by culturing the cells with c-lactam of hydroxycobalamin (c-lactam OH-Cbl). We revealed a non-apoptotic activation of caspases (3/7, 8, 9) in cobalamin-deficient NHA, which may suggest astrogliosis. The aim of the current study was to experimentally verify this hypothesis. We indicated an increase in the cellular expression of two astrogliosis markers: glial fibrillary acidic protein and vimentin in cobalamin-deficient NHA using Western blot analysis and immunocytochemistry with confocal laser scanning microscopy. In the next step of the study, we revealed c-lactam OH-Cbl as a potential non-toxic vitamin B12 antagonist in an in vivo model using zebrafish embryos. We believe that the presented results will contribute to a better understanding of the cellular mechanism underlying neurologic pathology due to cobalamin deficiency and will serve as a foundation for further studies

Lower extremity muscle strength, postural stability and functional movement screen in female basketball players after ACL reconstruction : Preliminary report

The anterior cruciate ligament (ACL) tear is a common injury in basketball. Its consequence is a long absence from training, resulting from surgical treatment and long physiotherapy. The aim of the study was to assess muscle strength, postural stability and functional movements in female basketball players, who returned to professional sport careers after anterior cruciate ligament reconstruction. Methods: The study population consisted of 10 female basketball players after surgical reconstruction of anterior cruciate ligament. The control group consisted of 10 players without ACL injury. We used the Biodex System 4 Pro dynamometer to assess the muscle strength of the knee. We used it to conduct the test of flexors and extensors of the knee in isokinetic conditions. We also used Keiser Power Squat A300 in the single leg squat to measure power and the Biodex Balance SD dynamographic platform to assess balance in single leg stance. Results: We found deficits in both movement patterns and in muscle strength in the study population, compared to control group. Conclusions: The basketball players after ACL reconstruction had significant differences between the operated and non-operated limb. The differences may predispose them towards repeated ACL injuries

Synthesis and Anticancer Activity of Indole-Functionalized Derivatives of Betulin

Pentacyclic triterpenes, including betulin, are widespread natural products with various pharmacological effects. These compounds are the starting material for the synthesis of substances with promising anticancer activity. The chemical modification of the betulin scaffold that was carried out as part of the research consisted of introducing the indole moiety at the C-28 position. The synthesized new 28-indole-betulin derivatives were evaluated for anticancer activity against seven human cancer lines (A549, MDA-MB-231, MCF-7, DLD-1, HT-29, A375, and C32). It was observed that MCF-7 breast cancer cells were most sensitive to the action of the 28-indole-betulin derivatives. The study shows that the lup-20(29)-ene-3-ol-28-yl 2-(1H-indol-3-yl)acetate caused the MCF-7 cells to arrest in the G1 phase, preventing the cells from entering the S phase. The performed cytometric analysis of DNA fragmentation indicates that the mechanism of EB355A action on the MCF-7 cell line is related to the induction of apoptosis. An in silico ADMET profile analysis of EB355A and EB365 showed that both compounds are bioactive molecules characterized by good intestinal absorption. In addition, the in silico studies indicate that the 28-indole-betulin derivatives are substances of relatively low toxicity

Drug-Induced Photosensitivity—From Light and Chemistry to Biological Reactions and Clinical Symptoms

Photosensitivity is one of the most common cutaneous adverse drug reactions. There are two types of drug-induced photosensitivity: photoallergy and phototoxicity. Currently, the number of photosensitization cases is constantly increasing due to excessive exposure to sunlight, the aesthetic value of a tan, and the increasing number of photosensitizing substances in food, dietary supplements, and pharmaceutical and cosmetic products. The risk of photosensitivity reactions relates to several hundred externally and systemically administered drugs, including nonsteroidal anti-inflammatory, cardiovascular, psychotropic, antimicrobial, antihyperlipidemic, and antineoplastic drugs. Photosensitivity reactions often lead to hospitalization, additional treatment, medical management, decrease in patient’s comfort, and the limitations of drug usage. Mechanisms of drug-induced photosensitivity are complex and are observed at a cellular, molecular, and biochemical level. Photoexcitation and photoconversion of drugs trigger multidirectional biological reactions, including oxidative stress, inflammation, and changes in melanin synthesis. These effects contribute to the appearance of the following symptoms: erythema, swelling, blisters, exudation, peeling, burning, itching, and hyperpigmentation of the skin. This article reviews in detail the chemical and biological basis of drug-induced photosensitivity. The following factors are considered: the chemical properties, the influence of individual ranges of sunlight, the presence of melanin biopolymers, and the defense mechanisms of particular types of tested cells

UVA Radiation Enhances Lomefloxacin-Mediated Cytotoxic, Growth-Inhibitory and Pro-Apoptotic Effect in Human Melanoma Cells through Excessive Reactive Oxygen Species Generation

Melanoma, the most dangerous type of cutaneous neoplasia, contributes to about 75% of all skin cancer-related deaths. Thus, searching for new melanoma treatment options is an important field of study. The current study was designed to assess whether the condition of mild and low-dose UVA radiation augments the lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effect of the drug in melanoma cancer cells through excessive oxidative stress generation. C32 amelanotic and COLO829 melanotic (BRAF-mutant) melanoma cell lines were used as an experimental model system. The combined exposure of cells to both lomefloxacin and UVA irradiation caused higher alterations of redox signalling pathways, as shown by intracellular reactive oxygen species overproduction and endogenous glutathione depletion when compared to non-irradiated but lomefloxacin-treated melanoma cells. The obtained results also showed that lomefloxacin decreased both C32 and COLO829 cells’ viability in a concentration-dependent manner. This effect significantly intensified when melanoma cells were exposed to UVA irradiation and the drug. For melanoma cells exposed to lomefloxacin or lomefloxacin co-treatment with UVA irradiation, the concentrations of the drug that decreased the cells’ viability by 50% (EC50) were found to be 0.97, 0.17, 1.01, 0.18 mM, respectively. Moreover, we found that the redox imbalance, mitochondrial membrane potential breakdown, induction of DNA fragmentation, and changes in the melanoma cells’ cell cycle distribution (including G2/M, S as well as Sub-G1-phase blockade) were lomefloxacin in a dose-dependent manner and were significantly augmented by UVA radiation. This is the first experimental work that assesses the impact of excessive reactive oxygen species generation upon UVA radiation exposure on lomefloxacin-mediated cytotoxic, growth-inhibitory and pro-apoptotic effects towards human melanoma cells, indicating the possibility of the usage of this drug in the photochemotherapy of malignant melanoma as an innovative medical treatment option which could improve the effectiveness of therapy. The obtained results also revealed that the redox imbalance intensification mediated by the phototoxic potential of fluoroquinolones may be considered as a more efficient treatment model of malignant melanoma and may constitute the basis for the development of new compounds with a high ability to excessive oxidative stress generation upon UVA radiation in cancer cells

Cellular and Molecular Aspects of Anti-Melanoma Effect of Minocycline—A Study of Cytotoxicity and Apoptosis on Human Melanotic Melanoma Cells

Minocycline is a tetracycline compound with pleiotropic pharmacological properties. In addition to its antibacterial action, it shows many non-antimicrobial effects, including an anti-cancer activity. The anti-cancer action was confirmed in studies on ovarian carcinoma cells, hepatocellular carcinoma cells, glioma cells, or acute myeloid leukemia cells. Malignant melanoma remains a serious medical problem despite the extensive knowledge of the disease. The low effectiveness of the standard treatment, as well as the resistance to therapy, result in high mortality rates. This work aimed to investigate the potential and mechanisms of anti-melanoma action of minocycline. Human skin melanotic melanoma cell line COLO 829 was used in the study. The obtained results showed that minocycline decreased cell viability and inhibited the growth of melanoma cells, proportional to the drug concentration as well as to the time of incubation. The EC50 values were calculated to be 78.6 µM, 31.7 µM, and 13.9 µM for 24 h, 48 h, and 72 h, respectively. It was observed that treated cells had a disturbed cell cycle and significantly changed morphology. Moreover, minocycline caused a decrease in mitochondrial membrane potential and an increase in cells with a low level of reduced thiols. Finally, it was found that the anti-melanoma effect of minocycline was related to the induction of apoptosis. The drug activated caspases 8, 9, and 3/7 as well as increased the number of annexin V-positive cells. The presented results show that minocycline possesses anti-melanoma potential

The Assessment of the Phototoxic Action of Chlortetracycline and Doxycycline as a Potential Treatment of Melanotic Melanoma—Biochemical and Molecular Studies on COLO 829 and G-361 Cell Lines

Melanoma is still one of the most dangerous cancers. New methods of treatment are sought due to its high aggressiveness and the relatively low effectiveness of therapies. Tetracyclines are drugs exhibiting anticancer activity. Previous studies have also shown their activity against melanoma cells. The possibility of tetracycline accumulation in pigmented tissues and the increase in their toxicity under the influence of UVA radiation creates the possibility of developing a new anti-melanoma therapy. This study aimed to analyze the phototoxic effect of doxycycline and chlortetracycline on melanotic melanoma cells COLO 829 and G-361. The results indicated that tetracycline-induced phototoxicity significantly decreased the number of live cells by cell cycle arrest as well as a decrease in cell viability. The simultaneous exposure of cells to drugs and UVA caused the depolarization of mitochondria as well as inducing oxidative stress and apoptosis. It was found that the combined treatment activated initiator and effector caspases, caused DNA fragmentation and elevated p53 level. Finally, it was concluded that doxycycline demonstrated a stronger cytotoxic and phototoxic effect. UVA irradiation of melanoma cells treated with doxycycline and chlortetracycline allows for the reduction of therapeutic drug concentrations and increases the effectiveness of tested tetracyclines

Cobalamin Deficiency May Induce Astrosenescence—An In Vitro Study

Cobalamin (vitamin B12) deficiency is one of the major factors causing degenerative changes in the nervous system and, thus, various neurological and psychiatric symptoms. The underlying cellular mechanism of this phenomenon is not yet fully understood. An accumulation of senescent astrocytes has been shown to contribute to a wide range of pathologies of the nervous system, including neurodegenerative disorders. This study aimed to investigate whether cobalamin deficiency triggers astrosenescence. After inducing cobalamin deficiency in normal human astrocytes in vitro, we examined biomarkers of cellular senescence: SA-β-gal, p16INK4A, and p21Waf1/Cip1 and performed cell nuclei measurements. The obtained results may contribute to an increase in the knowledge of the cellular effects of cobalamin deficiency in the context of astrocytes. In addition, the presented data suggest a potential causative agent of astrosenescence that has not been proven to date