Structure, Antioxidant Activity and Antimicrobial Study of Light Lanthanide Complexes with p-Coumaric Acid.

This paper presents the results of a study of the effects of the lanthanide ions Ce3+, Pr3+, Nd3+ and Sm3+ on the electronic structure and antioxidant and biological (antimicrobial and cytotoxic) properties of p-coumaric acid (p-CAH2). Structural studies were conducted via spectroscopic methods (FTIR, ATR, UV). Thermal degradation studies of the complexes were performed. The results are presented in the form of TG, DTG and DSC curves. Antioxidant properties were determined via activity tests against DPPH, ABTS and OH radicals. The reducing ability was tested via CUPRAC assays. Minimum inhibitory concentrations (MICs) of the ligand and lanthanide complexes were determined on E. coli, B. subtilis and C. albicans microorganisms. The antimicrobial activity was also determined using the MTT assay. The results were presented as the relative cell viability of C. albicans, P. aeruginosa, E. coli and S. aureus compared to controls and expressed as percentages. In the obtained complexes in the solid phase, lanthanide ions coordinate three ligands in a bidentate chelating coordination mode through the carboxyl group of the acid. Spectroscopic analysis showed that lanthanide ions increase the aromaticity of the pi electron system of the ligand. Thermal analysis showed that the complexes are hydrated and have a higher thermal stability than the ligand. The products of thermal decomposition of the complexes are lanthanide oxides. In the aqueous phase, the metal combines with the ligand in a 1:1 molar ratio. Antioxidant activity tests showed that the complexes have a similar ability to remove free radicals. ABTS and DPPH tests showed that the complexes have twice the ability to neutralise radicals than the ligand, and a much higher ability to remove the hydroxyl radical. The abilities of the complexes and the free ligand to reduce Cu2+ ions in the CUPRAC test are at a similar level. Lanthanide complexes of p-coumaric acid are characterised by a higher antimicrobial capacity than the free ligand against Escherichia coli bacteria, Bacillus subtilis and Candida albicans fungi.

The Impact of Glycolysis and Its Inhibitors on the Immune Response to Inflammation and Autoimmunity.

Glucose metabolism is a crucial biological pathway maintaining the activation of extra- and intracellular signaling pathways involved in the immune response. Immune cell stimulation via various environmental factors results in their activation and metabolic reprogramming to aerobic glycolysis. Different immune cells exhibit cell-type-specific metabolic patterns when performing their biological functions. Numerous published studies have shed more light on the importance of metabolic reprogramming in the immune system. Moreover, this knowledge is crucial for revealing new ways to target inflammatory pathologic states, such as autoimmunity and hyperinflammation. Here, we discuss the role of glycolysis in immune cell activity in physiological and pathological conditions, and the potential use of inhibitors of glycolysis for disease treatment.

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

d-Glucose- and d-mannose-based antimetabolites. Part 4: Facile synthesis of mono- and di-acetates of 2-deoxy-d-glucose prodrugs as potentially useful antimetabolites.

2-Deoxy-d-glucose (2-DG), a compound known to interfere with d-glucose and d-mannose metabolism, has been tested as a potential anticancer and antiviral agent. Preclinical and clinical studies focused on 2-DG have highlighted several limitations related to 2-DG drug-like properties, such as poor pharmacokinetic properties. To overcome this problem, we proposed design and synthesis of novel 2-DG prodrugs that subsequently could be tested using a variety of biochemical and molecular methods. We narrowed here our focus to esters of 2-DG as potential prodrugs based on the hypothesis that ubiquitous esterases will regenerate 2-DG, leading to increased circulation time of drug and adequate organ and tumor penetration. Testing this hypothesis in vitro and, especially, in vivo requires significant amounts of respective pure mono- and previously unknown di-acetylated water-soluble derivatives of 2-DG. Development of their efficient and practical method of synthesis was imperative. We describe novel facile and scalable syntheses of seven selectively acetylated water-soluble derivatives of 2-DG and present a detailed 1H and 13C NMR analysis of all final products. X-ray diffraction analysis has been performed for compound WP1122 that was selected for detailed preclinical and subsequent clinical evaluation as potential anticancer or antiviral agent.

Collagen matrix scaffolds: Future perspectives for the management of chronic liver diseases.

Approximately 1.5 billion chronic liver disease (CLD) cases have been estimated worldwide, encompassing a wide range of liver damage severities. Moreover, liver disease causes approximately 1.75 million deaths per year. CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process, cell death, over deposition of extracellular matrix proteins, and dysregulated regeneration. Overall, these processes impair the correct function of this vital organ. Cirrhosis and liver cancer are the main complications of CLD, which accounts for 3.5% of all deaths worldwide. Liver transplantation is the optimal therapeutic option for advanced liver damage. The liver is one of the most common organs transplanted; however, only 10% of liver transplants are successful. In this context, regenerative medicine has made significant progress in the design of biomaterials, such as collagen matrix scaffolds, to address the limitations of organ transplantation (e.g., low donation rates and biocompatibility). Thus, it remains crucial to continue with experimental and clinical studies to validate the use of collagen matrix scaffolds in liver disease.

Anthracycline-induced cardiotoxicity - are we about to clear this hurdle?

Anthracyclines have contributed significantly to remarkable improvements in overall survival and are regarded as the most effective cytostatic drug for cancer treatment in various malignancies. However, anthracyclines are a significant cause of acute and chronic cardiotoxicity in cancer patients, and long-term cardiotoxicity can lead to death in about one-third of patients. Several molecular pathways have been implicated in the development of anthracycline-induced cardiotoxicity, although the underlying mechanisms of some molecular pathways are not fully elucidated. It is now generally believed that anthracycline-induced reactive oxygen species (resulting from intracellular metabolism of anthracyclines) and drug-induced inhibition of topoisomerase II beta are the key mechanisms responsible for the cardiotoxicity. To prevent cardiotoxicity, several strategies are being followed: (i) angiotensin-converting enzyme inhibitors, sartans, beta-blockers, aldosterone antagonists, and statins; (ii) iron chelators; and (iii) by development of new anthracycline derivatives with little or no cardiotoxicity. This review will discuss clinically evaluated doxorubicin analogues that were developed as potentially non-cardiotoxic anticancer agents and include recent development of a novel liposomal anthracycline (L-Annamycin) for the treatment of soft-tissue sarcoma metastatic to the lung and acute myelogenous leukaemia.

Development of a Novel Tool To Demystify Drug Distribution at Tissue-Blood Barriers.

Tissue endothelial cells express ABC-transporter enzymes that change the concentration of small molecules within different tissue compartments. These "blood-tissue barriers" have been shown to directly affect the efficacy and toxicity of anticancer, antimicrobial, psychiatric, and anti-epileptic drugs. Currently this phenomenon is best studied for the blood-brain barrier, but remains enigmatic for most other tissues. In addition, canonical pharmacokinetic theory specifically assumes an equal concentration of free drug within all tissue compartments. Inspired by Lipinski's "rule of 5," we here clarify current knowledge on drug-tissue distribution by: 1) curating the in-vivo literature on 73 drugs across 23 tissues and 2) developing two graphical web-based applications to visually describe and interpret data. These curated in-vivo dataset and visualization tools enabled us to achieve new insights into the logic of the barrier-tissue organization and showed remarkable correspondence to whole-body imaging of radiolabeled molecules.

MEETING HIGHLIGHTS: THE THIRD MARIE SKLODOWSKA-CURIE SYMPOSIUM ON CANCER RESEARCH AND CARE AT ROSWELL PARK COMPREHENSIVE CANCER CENTER, BUFFALO, NY, SEPTEMBER 20-22, 2023.

Marie Sklodowska-Curie Symposia on Cancer Research and Care (MSCS-CRC) promote collaborations between cancer researchers and care providers in the United States, Canada and Central and Eastern European Countries (CEEC), to accelerate the development of new cancer therapies, advance early detection and prevention, increase cancer awareness, and improve cancer care and the quality of life of patients and their families. The third edition of MSCS-CRC, held at Roswell Park Comprehensive Cancer Center, Buffalo, NY, in September 2023, brought together 137 participants from 20 academic institutions in the US, Poland, Ukraine, Lithuania, Croatia and Hungary, together with 16 biotech and pharma entities. The key areas of collaborative opportunity identified during the meeting are a) creating of a database of available collaborative projects in the areas of early-phase clinical trials, preclinical development, and identification of early biomarkers; b) promoting awareness of cancer risks and efforts at cancer prevention; c) laboratory and clinical training; and d) sharing experience in cost-effective delivery of cancer care and improving the quality of life of cancer patients and their families. Examples of ongoing international collaborations in the above areas were discussed. Participation of the representatives of the Warsaw-based Medical Research Agency, National Cancer Institute (NCI) of the United States, National Cancer Research Institutes of Poland and Lithuania, New York State Empire State Development, Ministry of Health of Ukraine and Translational Research Cancer Center Consortium of 13 cancer centers from the US and Canada, facilitated the discussion of available governmental and non-governmental funding initiatives in the above areas.

The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses.

Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.

A first-in-human Phase I trial of the oral p-STAT3 inhibitor WP1066 in patients with recurrent malignant glioma.

Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2 was 2-3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

X-ray wavefunction refinement and comprehensive structural studies on bromo-substituted analogues of 2-deoxy-d-glucose in solid state and solution.

The structural studies on two bromo-substituted derivatives of 2-deoxy-d-glucose (2-DG), namely 2-deoxy-2-bromo-d-glucose (2-BG) and 2-deoxy-2-bromo-d-mannose (2-BM) are described. 2-DG itself is an inhibitor of hexokinase, the first enzyme in the glycolysis process, playing a vital role in both cancer cell metabolism and viral replication in host cells. Because of that, 2-DG derivatives are considered as potential anti-cancer and anti-viral drugs. An X-ray quantum crystallography approach allowed us to obtain more accurate positions of hydrogen atoms by applying Hirshfeld atom refinement, providing a better description of hydrogen bonding even in the case of data from routine X-ray experiments. Obtained structures showed that the introduction of bromine at the C2 position in the pyranose ring has a minor influence on its conformation but still, it has a noticeable effect on the crystal structure. Bromine imposes the formation of a layered supramolecular landscape containing hydrogen bonds, which involves the bromine atom. Periodic DFT calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings and highlighted energetic changes upon bromine substitution. Based on molecular wavefunction from the refinement, we calculated the electrostatic potential, Laplacian, and ELI-D, and applied them to charge-density studies, which confirmed the geometry of hydrogen bonding and involvement of the bromine atom with these intermolecular interactions. NMR studies in the solution show that both compounds do not display significant differences in their anomeric equilibria compared to 2-DG, and the pyranose ring puckering is similar in both aqueous and solid state.

Correction: X-ray wavefunction refinement and comprehensive structural studies on bromo-substituted analogues of 2-deoxy-d-glucose in solid state and solution.

[This corrects the article DOI: 10.1039/D1RA08312K.].

TARGETED DOWN REGULATION OF CORE MITOCHONDRIAL GENES DURING SARS-COV-2 INFECTION.

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19.

Synergistic Anticancer Effect of Glycolysis and Histone Deacetylases Inhibitors in a Glioblastoma Model.

Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy.

Role of miR-2392 in driving SARS-CoV-2 infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.

Plant-Derived and Dietary Hydroxybenzoic Acids-A Comprehensive Study of Structural, Anti-/Pro-Oxidant, Lipophilic, Antimicrobial, and Cytotoxic Activity in MDA-MB-231 and MCF-7 Cell Lines.

Seven derivatives of plant-derived hydroxybenzoic acid (HBA)-including 2,3-dihydroxybenzoic (2,3-DHB, pyrocatechuic), 2,4-dihydroxybenzoic (2,4-DHB, ß-resorcylic), 2,5-dihydroxybenzoic (2,5-DHB, gentisic), 2,6-dihydroxybenzoic (2,6-DHB, γ-resorcylic acid), 3,4-dihydroxybenzoic (3,4-DHB, protocatechuic), 3,5-dihydroxybenzoic (3,5-DHB, α-resorcylic), and 3,4,5-trihydroxybenzoic (3,4,5-THB, gallic) acids-were studied for their structural and biological properties. Anti-/pro-oxidant properties were evaluated by using DPPH• (2,2-diphenyl-1-picrylhydrazyl), ABTS•+ (2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), FRAP (ferric-reducing antioxidant power), CUPRAC (cupric-reducing antioxidant power), and Trolox oxidation assays. Lipophilicity was estimated by means of experimental (HPLC) and theoretical methods. The antimicrobial activity against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), Salmonella enteritidis (S. enteritidis), and Candida albicans (C. albicans) was studied. The cytotoxicity of HBAs in MCF-7 and MDA-MB-231 cell lines was estimated. Moreover, the structure of HBAs was studied by means of experimental (FTIR, 1H, and 13C NMR) and quantum chemical DFT methods (the NBO and CHelpG charges, electrostatic potential maps, and electronic parameters based on the energy of HOMO and LUMO orbitals). The aromaticity of HBA was studied based on the calculated geometric and magnetic aromaticity indices (HOMA, Aj, BAC, I6, NICS). The biological activity of hydroxybenzoic acids was discussed in relation to their geometry, the electronic charge distribution in their molecules, their lipophilicity, and their acidity. Principal component analysis (PCA) was used in the statistical analysis of the obtained data and the discussion of the dependency between the structure and activity (SAR: structure-activity relationship) of HBAs. This work provides valuable information on the potential application of hydroxybenzoic acids as bioactive components in dietary supplements, functional foods, or even drugs.

The Great Deceiver: miR-2392's Hidden Role in Driving SARS-CoV-2 Infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia as well as promoting many symptoms associated with COVID-19 infection. We demonstrate miR-2392 is present in the blood and urine of COVID-19 positive patients, but not detected in COVID-19 negative patients. These findings indicate the potential for developing a novel, minimally invasive, COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we have developed a novel miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters and may potentially inhibit a COVID-19 disease state in humans.

Experimental and Computational Studies on Structure and Energetic Properties of Halogen Derivatives of 2-Deoxy-D-Glucose.

The results of structural studies on a series of halogen-substituted derivatives of 2-deoxy-D-glucose (2-DG) are reported. 2-DG is an inhibitor of glycolysis, a metabolic pathway crucial for cancer cell proliferation and viral replication in host cells, and interferes with D-glucose and D-mannose metabolism. Thus, 2-DG and its derivatives are considered as potential anticancer and antiviral drugs. X-ray crystallography shows that a halogen atom present at the C2 position in the pyranose ring does not significantly affect its conformation. However, it has a noticeable effect on the crystal structure. Fluorine derivatives exist as a dense 3D framework isostructural with the parent compound, while Cl- and I-derivatives form layered structures. Analysis of the Hirshfeld surface shows formation of hydrogen bonds involving the halogen, yet no indication for the existence of halogen bonds. Density functional theory (DFT) periodic calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings. NMR studies in the solution show that most of the compounds do not display significant differences in their anomeric equilibria, and that pyranose ring puckering is similar to the crystalline state. For 2-deoxy-2-fluoro-D-glucose (2-FG), electrostatic interaction energies between the ligand and protein for several existing structures of pyranose 2-oxidase were also computed. These interactions mostly involve acidic residues of the protein; single amino-acid substitutions have only a minor impact on binding. These studies provide a better understanding of the structural chemistry of halogen-substituted carbohydrates as well as their intermolecular interactions with proteins determining their distinct biological activity.

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.