Investigation of the potential effects of estrogen receptor modulators on immune checkpoint molecules.

Immune checkpoints regulate the immune system response. Recent studies suggest that flavonoids, known as phytoestrogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (SERMs) as inhibiting ligands for immune checkpoint proteins (CTLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong binding energy values for quinestrol, quercetin, and bazedoxifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin and bazedoxifene, known to modulate EGFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functionality. We discuss the impact of SERMs on PD-1 and CTLA-4, suggesting that these SERMs could have therapeutic effects through immune checkpoint inhibition. This study highlights the potential of SERMs as inhibitory ligands for immune checkpoint proteins, emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating SERMs as therapeutic agents. Our findings open new avenues for cancer immunotherapy by exploring the interaction between various SERMs and immune checkpoint pathways.

The Role of Angiotensin-Converting Enzyme (ACE) Polymorphisms in the Risk of Development and Treatment of Diabetic Nephropathy.

BACKGROUND: Angiotensin-converting enzyme (ACE) is responsible for the production of angiotensin II, and increased production of angiotensin II is observed in diabetes. What is more, ACE polymorphisms may play a role in the development of diabetic nephropathy. The aim of this study was to assess the role of selected ACE polymorphisms (rs4343 and rs4646994) in the risk of development of diabetic nephropathy and in the likelihood of renal replacement therapy. METHODS: ACE polymorphisms were analyzed in a group of 225 patients who were divided into three subgroups. The rs4343 polymorphism was determined using the PCR-RFLP, and the rs4646994 polymorphism was determined using the PCR. Molecular docking between domains of ACE and its ligands was performed by using AutoDock Vina. RESULTS: The G/G genotype of rs4343 polymorphism is associated with increased odds of developing diabetic nephropathy. The G allele is also associated with a higher risk of this disease. Similar results were obtained in patients who had already had a kidney transplant as a result of diabetic nephropathy. CONCLUSIONS: The presence of G/G and G/A genotypes, and the G allele increases the likelihood of developing diabetic nephropathy. This may also be a risk factor for renal replacement therapy.

Combination of quinoxaline with pentamethinium system: Mitochondrial staining and targeting.

Pentamethinium indolium salts are promising fluorescence probes and anticancer agents with high mitochondrial selectivity. We synthesized two indolium pentamethinium salts: a cyclic form with quinoxaline directly incorporated in the pentamethinium chain (cPMS) and an open form with quinoxaline substitution in the γ-position (oPMS). To better understand their properties, we studied their interaction with mitochondrial phospholipids (cardiolipin and phosphatidylcholine) by spectroscopic methods (UV-Vis, fluorescence, and NMR spectroscopy). Both compounds displayed significant affinity for cardiolipin and phosphatidylcholine, which was associated with a strong change in their UV-Vis spectra. Nevertheless, we surprisingly observed that fluorescence properties of cPMS changed in complex with both cardiolipin and phosphatidylcholine, whereas those of oPMS only changed in complex with cardiolipin. Both salts, especially cPMS, display high usability in mitochondrial imaging and are cytotoxic for cancer cells. The above clearly indicates that conjugates of pentamethinium and quinoxaline group, especially cPMS, represent promising structural motifs for designing mitochondrial-specific agents.

TET protein inhibitors: Potential and limitations.

TET proteins (methylcytosine dioxygenases) play an important role in the regulation of gene expression. Dysregulation of their activity is associated with many serious pathogenic states such as oncological diseases. Regulation of their activity by specific inhibitors could represent a promising therapeutic strategy. Therefore, this review describes various types of TET protein inhibitors in terms of their inhibitory mechanism and possible applicability. The potential and possible limitations of this approach are thoroughly discussed in the context of TET protein functionality in living systems. Furthermore, possible therapeutic strategies based on the inhibition of TET proteins are presented and evaluated, especially in the field of oncological diseases.

Azulene hydrazide-hydrazones for selective targeting of pancreatic cancer cells.

Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.

Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration.

Mitochondria generate energy and building blocks required for cellular growth and function. The notion that mitochondria are not involved in the cancer growth has been challenged in recent years together with the emerging idea of mitochondria as a promising therapeutic target for oncologic diseases. Pentamethinium salts, cyan dyes with positively charged nitrogen on the benzothiazole or indole part of the molecule, were originally designed as mitochondrial probes. In this study, we show that pentamethinium salts have a strong effect on mitochondria, suppressing cancer cell proliferation and migration. This is likely linked to the strong inhibitory effect of the salts on dihydroorotate dehydrogenase (DHODH)-dependent respiration that has a key role in the de novo pyrimidine synthesis pathway. We also show that pentamethinium salts cause oxidative stress, redistribution of mitochondria, and a decrease in mitochondria mass. In conclusion, pentamethinium salts present novel anti-cancer agents worthy of further studies.

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators.

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 µM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.

New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts 5 and 6 (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of binding -9.5 and -8.1 kcal/mol). The interaction with IL-6R was confirmed using microscale thermophoresis analyses, which revealed that both compounds had strong affinity for the IL-6R (experimentally determined dissociation constants 26.5 ± 2.5 nM and 304 ± 27.6 nM, respectively). In addition, both compounds were cytotoxic for a broad spectrum of cancer cell lines in micromolar concentrations, most likely due to their accumulation in mitochondria and inhibition of mitochondrial respiration. In summary, the structure motif of bis-pentamethinium salts represents a promising starting point for the design of novel multitargeting compounds with the potential to inhibit IL-6 signaling and simultaneously target mitochondrial metabolism in cancer cells.

Non-psychotropic cannabinoids as inhibitors of TET1 protein.

Non-psychotropic cannabinoids (e.g., cannabidiol, cannabinol and cannabigerol) are contained in numerous alimentary and medicinal products. Therefore, predicting and studying their possible side effects, such as changes in DNA methylation, is an important task for assessing the safety of these products. Interference with TET enzymes by chelating ferrous ions can contribute to the altered methylation pattern. All tested cannabinoids displayed a strong affinity for Fe(II) ions. Cannabidiol and cannabinol exhibited potent inhibitory activities (IC50 = 4.8 and 6.27 µM, respectively) towards the TET1 protein, whereas cannabigerol had no effect on the enzyme activity. An in silico molecular docking study revealed marked binding potential within the catalytic cavity for CBD/CBN, but some affinity was also found for CBG, thus the total lack of activity remains unexplained. These results imply that cannabinoids could affect the activity of the TET1 protein not only due to their affinity for Fe(II) but also due to other types of interactions (e.g., hydrophobic interactions and hydrogen bonding).

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design.

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial-mesenchymal transition, and migration of cancer cells).

Estrogen Receptor Modulators in Viral Infections Such as SARS-CoV-2: Therapeutic Consequences.

COVID-19 is a pandemic respiratory disease caused by the SARS-CoV-2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal.

Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water.

Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.