The physiological concentration of ferrous iron (II) alters the inhibitory effect of hydrogen peroxide on CD45, LAR and PTP1B phosphatases

Hydrogen peroxide is an important regulator of protein tyrosine phosphatase activity via reversible oxidation. However, the role of iron in this reaction has not been yet elucidated. Here we compare the influence of hydrogen peroxide and the ferrous iron (reagent for Fenton reaction) on the enzymatic activity of recombinant CD45, LAR, PTP1B phosphatases and cellular CD45 in Jurkat cells. The obtained results show that ferrous iron (II) is potent inhibitor of CD45, LAR and PTP1B, but the inhibitory effect is concentration dependent. We found that the higher concentrations of ferrous iron (II) increase the inactivation of CD45, LAR and PTP1B phosphatase caused by hydrogen peroxide, but the addition of the physiological concentration (500 nM) of ferrous iron (II) has even a slightly preventive effect on the phosphatase activity against hydrogen peroxide

Green Tea Catechins Induce Inhibition of PTP1B Phosphatase in Breast Cancer Cells with Potent Anti-Cancer Properties: In Vitro Assay, Molecular Docking, and Dynamics Studies

The catechins derived from green tea possess antioxidant activity and may have a potentially anticancer effect. PTP1B is tyrosine phosphatase that is oxidative stress regulated and is involved with prooncogenic pathways leading to the formation of a.o. breast cancer. Here, we present the effect of selected green tea catechins on enzymatic activity of PTP1B phosphatase and viability of MCF-7 breast cancer cells. We showed also the computational analysis of the most effective catechin binding with a PTP1B molecule. We observed that epigallocatechin, epigallocatechin gallate, epicatechin, and epicatechin gallate may decrease enzymatic activity of PTP1B phosphatase and viability of MCF-7 cells. Conclusions: From the tested compounds, epigallocatechin and epigallocatechin gallate were the most effective inhibitors of the MCF-7 cell viability. Moreover, epigallocatechin was also the strongest inhibitor of PTP1B activity. Computational analysis allows us also to conclude that epigallocatechin is able to interact and bind to PTP1B. Our results suggest also the most predicted binding site to epigallocatechin binding to PTP1B

Docosahexaenoic Acid Inhibits PTP1B Phosphatase and the Viability of MCF-7 Breast Cancer Cells

Background: Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid compound present in deep water fishes and dietary supplements, with a wide spectrum of potential health benefits, ranging from neurological to anti-inflammatory. Methods: Due to the fact that DHA is considered a breast cancer risk reducer, we examined the impact of DHA on MCF-7 breast cancer cells’ viability and its inhibitory properties on protein tyrosine phosphatase 1B (PTP1B), a pro-oncogenic phosphatase. Results: We found that DHA is able to lower both the enzymatic activity of PTP1B phosphatase and the viability of MCF-7 breast cancer cells. We showed that unsaturated DHA possesses a significantly higher inhibitory activity toward PTP1B in comparison to similar fatty acids. We also performed a computational analysis of DHA binding to PTP1B and discovered that it is able to bind to an allosteric binding site. Conclusions: Utilizing both a recombinant enzyme and cellular models, we demonstrated that DHA can be considered a potential pharmacological agent for the prevention of breast cancer

Bacterial Protein Tyrosine Phosphatases as Possible Targets for Antimicrobial Therapies in Response to Antibiotic Resistance

The review is focused on the bacterial protein tyrosine phosphatases (PTPs) utilized by bacteria as virulence factors necessary for pathogenicity. The inhibition of bacterial PTPs could contribute to the arrest of the bacterial infection process. This mechanism could be utilized in the design of antimicrobial therapy as adjuvants to antibiotics. The review summaries knowledge on pathogenic bacterial protein tyrosine phosphatases (PTPs) involved in infection process, such as: PTPA and PTPB from Staphylococcus aureus and Mycobacterium tuberculosis; SptP from Salmonella typhimurium; YopH from Yersinia sp. and TbpA from Pseudomonas aeruginosa. The review focuses also on the potential inhibitory compounds of bacterial virulence factors and inhibitory mechanisms such as the reversible oxidation of tyrosine phosphatases

Beneficial Properties of Green Tea Catechins

Green tea (Camellia sinesis) is widely known for its anticancer and anti-inflammatory properties. Among the biologically active compounds contained in Camellia sinesis, the main antioxidant agents are catechins. Recent scientific research indicates that the number of hydroxyl groups and the presence of characteristic structural groups have a major impact on the antioxidant activity of catechins. The best source of these compounds is unfermented green tea. Depending on the type and origin of green tea leaves, their antioxidant properties may be uneven. Catechins exhibit the strong property of neutralizing reactive oxygen and nitrogen species. The group of green tea catechin derivatives includes: epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate. The last of these presents the most potent anti-inflammatory and anticancer potential. Notably, green tea catechins are widely described to be efficient in the prevention of lung cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer and prostate cancer. The current review aims to summarize the potential anticancer effects and molecular signaling pathways of major green tea catechins. It needs to be clearly emphasized that green tea as well as green tea catechols cannot replace the standard chemotherapy. Nonetheless, their beneficial effects may support the standard anticancer approach

Biology and chemistry of lung cancer

Lung cancer is the most common fatal cancer disease in the world. A characteristic feature of lung cancer is genetic diversity. In the overwhelming majority of cases, smoking is the most important etiopathogenic factor. Lung cancer is a cancer with a very bad prognosis regarding long-term survival. The risk of lung cancer depends primarily on active or passive exposure to the carcinogenic components of tobacco smoke. According to available data, the development of lung cancer in addition to active and passive smoking is directly affected by environmental pollution such as smog and fumes, ionizing radiation, mycotoxins and long-term exposure to asbestos (occupational exposure). Research on the pharmacoprevention of lung cancer began over 30 years ago. The first nutrient that the researchers said could inhibit the development of lung cancer was beta carotene. Unfortunately, long-term regular supplementation with high doses of antioxidant in the form of beta-carotene brought the opposite effect. An increase in the incidence of lung cancer was found in people who received beta carotene in the form of a synthetic food supplement. The other component tested was N-acetylcysteine. It is a sulfur compound and a powerful antioxidant that supports the synthesis of glutathione and cysteine, with destructive effects on carcinogenic substances. N-acetyl-cysteine, used in the form of NAC adduct and epigallocatechin-3-gallate, showed efficacy in inhibiting the development of lung cancer only in animal models. In the pharmacoprevention of lung cancer, the use of vitamin E was also tested in the form of tocotrienol and tocopherol. The following work also shows the existence of a high concentration correlation which belongs to the steroid hormone, mainly estrogen, in the blood and the development of lung cancer in women. An increased risk of lung cancer has been observed in women undergoing long-term hormone replacement therapy. The results show that 2-methoxyestradiol, the endogenous metabolite of 17ß-estradiol, shows positive results that inhibit the growth of lung cancer cell lines. The aim of the work was to present the correlation between tobacco abuse and passive smoking and lung cancer, pharmacoprevention of lung cancer and the association of elevated estrogen concentration in women with an increased risk of lung cancer

2-methoxyestradiol affects mitochondrial biogenesis pathway and succinate dehydrogenase complex flavoprotein subunit a in osteosarcoma cancer cells

Dysregulation of mitochondrial pathways is implicated in several diseases, including cancer. Notably, mitochondrial respiration and mitochondrial biogenesis are favored in some invasive cancer cells, such as osteosarcoma. Hence, the aim of the current work was to investigate the effects of 2-methoxyestradiol (2-ME), a potent anticancer agent, on the mitochondrial biogenesis of osteosarcoma cells. Materials and Methods: Highly metastatic osteosarcoma 143B cells were treated with 2-ME separately or in combination with L-lactate, or with the solvent (non-treated control cells). Protein levels of α-syntrophin and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) were determined by western blotting. Impact of 2-ME on mitochondrial mass, regulation of cytochrome c oxidase I (COXI) expression, and succinate dehydrogenase complex flavoprotein subunit A (SDHA) was determined by immunofluorescence analyses. Inhibition of sirtuin 3 (SIRT3) activity by 2-ME was investigated by fluorescence assay and also, using molecular docking and molecular dynamics simulations. Results: Llactate induced mitochondrial biogenesis pathway via upregulation of COXI. 2-ME inhibited mitochondrial biogenesis via regulation of PGC-1�, COXI, and SIRT3 in a concentration-dependent manner as a consequence of nuclear recruitment of neuronal nitric oxide synthase and nitric oxide generation. It was also proved that 2-ME inhibited SIRT3 activity by binding to both the canonical and allosteric inhibitor binding sites. Moreover, regardless of the mitochondrial biogenesis pathway, 2-ME affected the expression of SDHA. Conclusion: Herein, mitochondrial biogenesis pathway regulation and SDHA were presented as novel targets of 2-ME, and moreover, 2-ME was demonstrated as a potent inhibitor of SIRT3. L-lactate was confirmed to exert pro-carcinogenic effects on osteosarcoma cells via the induction of the mitochondrial biogenesis pathway. Thus, L-lactate level may be considered as a prognostic biomarker for osteosarcom

Neuronal Nitric Oxide Synthase Induction in the Antitumorigenic and Neurotoxic Effects of 2-Methoxyestradiol

Objective: 2-Methoxyestradiol, one of the natural 17β-estradiol derivatives, is a novel, potent anticancer agent currently being evaluated in advanced phases of clinical trials. The main goal of the study was to investigate the anticancer activity of 2-methoxy-estradiol towards osteosarcoma cells and its possible neurodegenerative effects. We used an experimental model of neurotoxicity and anticancer activity of the physiological agent, 2-methoxyestradiol. Thus, we used highly metastatic osteosarcoma 143B and mouse immortalized hippocampal HT22 cell lines. The cells were treated with pharmacological (1 μM, 10 μM) concentrations of 2-methoxyestradiol. Experimental: Neuronal nitric oxide synthase and 3-nitrotyrosine protein levels were determined by western blotting. Cell viability and induction of cell death were measured by MTT and PI/Annexin V staining and a DNA fragmentation ELISA kit, respectively. Intracellular levels of nitric oxide were determined by flow cytometry. Results: Here we demonstrated that the signaling pathways of neurodegenerative diseases and cancer may overlap. We presented evidence that 2-methoxyestradiol, in contrast to 17β-estradiol, specifically affects neuronal nitric oxide synthase and augments 3-nitrotyrosine level leading to osteosarcoma and immortalized hippocampal cell death. Conclusions: We report the dual facets of 2-methoxyestradiol, that causes cancer cell death, but on the other hand may play a key role as a neurotoxin

Protein tyrosine phosphatases - factors of bacterial virulence : as a therapeutic target in response to increasing antibiotic resistance

Microbial virulence is the ability of pathogen to penetrate, replicate, multiplícate and, as a consequence, damage the cells of the infected organism. In recent years, rapid progress in bacterial genome sequencing has led to the discovery and characterization of many new virulence factors. One of the many mechanisms of bacterial virulence is the activity of bacterial kinases and phosphatases. These enzymes phosphorylate and dephosphorylate various amino acid residues in proteins, most commonly serine, tyrosine and threonine. Reversible phosphorylation and dephosphorylation can control the activity of target proteins, either directly, by inducing conformational changes in proteins, or indirectly, by regulating protein-protein interactions. Due to the increasing antibiotic resistance, new substances that could be used to treat diseases caused by resistant bacterial strains are sought. One of the possibilities seems to be the inhibition of bacterial tyrosine phosphatases. Phosphorylation of proteins containing tyrosine residues is a key post-translational modification that controls the numerous cellular functions in bacteria. So far, many tyrosine phosphatases have been found to be responsible for the virulence of various bacterial strains. Many bacterial species use protein tyrosine phosphatases activity in host-pathogen interaction, by affecting signalling pathways and subsequent induction of the infection process. Many studies are devoted to the search for tyrosine phosphatases inhibitors in the context of possible support of the current antibacterial treatment. This article presents a review of reports on bacterial virulence factors-protein tyrosine phosphatases as potential therapeutic targets