Search Results (54)

Lactate dehydrogenase (LDH) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate, with LDHA gaining particular attention for its overexpression in various malignancies and pivotal role in the Warburg effect-driven metabolic reprogramming. Elevated LDHA activity supports rapid ATP production under hypoxic conditions, maintains NAD⁺ regeneration, and promotes lactate accumulation, creating an acidic tumor microenvironment (TME) that favors invasion and immune evasion. Accumulating evidence demonstrates that LDHA is essential for primary tumor growth and critically involved in circulating tumor cell (CTC) survival, anoikis resistance, and metastatic spread. These functions are mediated by its regulation of adhesion molecules, cytoskeletal remodeling, and energy adaptation that enable CTCs to withstand mechanical shear stress and immune surveillance in the bloodstream. Pharmacological inhibition of LDHA, particularly via sodium oxamate (oxamate), has shown substantial potential in reducing metastasis and enhancing chemotherapy sensitivity in preclinical models. Oxamate has emerged as a promising candidate for metabolic cancer therapy due to its unique double effects on tumor metabolism and anti-tumor immunity, which are an advantage rarely highlighted in broader LDHA-focused reviews. This review synthesizes the molecular mechanisms through which LDHA drives tumor progression, dissects its context-specific functions in CTC biology, and evaluates the translational potential of LDHA-targeted strategies, with a focused emphasis on oxamate, as a transformative anti-metastatic therapeutic paradigm. By filling a critical gap in synthesizing oxamate’s distinct metabolic–immune regulatory actions, this work addresses an unmet need in the management of advanced, treatment-refractory cancers. Full article

Ammonium N-ethyloxamate (AmEtOxam) was synthesized, fully characterized by microanalytical and spectroscopic means, and assayed as a precursor of calcium oxalate, acting as a protecting agent for white Carrara marble. The monohydrate form of AmEtOxam shows a water solubility of 1.5 mol·L⁻¹ (~23% w/w), significantly higher than that of common calcium oxalate precursors (CaOx), such as ammonium oxalate (0.4 mol·L⁻¹, ~5% w/w). While AmEtOxam is stable in water solution and in the solid state in its monohydrate form, during the application on carbonate stone it undergoes a complete hydrolysis resulting in the formation of a uniform weddellite layer (CaC₂O₄·2H₂O) on carbonate stone surfaces. Application of 5% w/w aqueous solutions by spraying, brushing, and immersion resulted in different effects. Spraying yielded the most balanced performance, improving mechanical strength, reducing water absorption, recovering superficial tension, and limiting chromatic alteration. Brushing achieved significant gain in surface hardness with minimal esthetic impact. Immersion most effectively reduced porosity and increased surface tension. These results, coupled with the negligible chromatic changes induced in all cases, make AmEtOxam a promising candidate for the conservation of stone cultural heritage. Full article

The development of innovative technologies aimed at increasing agricultural crop yields through the use of growth regulators that incorporate various biologically active chemical moieties is a key focus in modern global agroscience. In this context, novel water-soluble silicon-organic compounds derived from carbamate (I) and oxamate (II) have been synthesised by the introduction of an organo-silicone fragment into these biologically active molecules. The compounds are O-isopropyl-N-(2-trimethylsilyloxyethyl)carbamate (III) and O-isopropyl-N-(2-trimethylsilyloxyethyl)oxamate (IV). It has been found that the 1 × 10⁻⁵ M water solutions of the compounds I–IV exhibited growth-regulating activity on the seeds of spring common wheat (Triticum aestivum L.). Laboratory studies demonstrated that the new silicon-containing compounds III and IV had a positive influence on the following: the germination potential, the seed germination, the length of roots, and the growth and development of shoots. Field tests revealed that spring wheat treatment with the compounds III and IV yielded an augmentation in spike length, an elevated quantity of grains per spike, and a grain mass per spike in comparison to the control. The application of compounds I–IV resulted in a significant enhancement in spring wheat yield. Full article

Hydrogen sulfide (H₂S) is a gasotransmitter that plays a crucial role in regulating pathological processes following injury to the central and peripheral nervous systems. This review systematizes current data on various classes of H₂S donors and inhibitors of its biosynthesis in neurotrauma and related experimental models. Inorganic donors (e.g., NaHS, Na₂S, and STS) rapidly suppress oxidative stress and inflammation, supporting the recovery of synaptic plasticity and cognitive function. Organic donors (e.g., GYY4137, ACS67, ACS84, SPRC, ADT-OH and its derivatives, S-memantine, and MTC) provide sustained H₂S release, stabilize the blood–brain barrier, and exhibit antiapoptotic activity. Natural donors (e.g., DADS, DATS, and SAMe) demonstrate high biocompatibility, inhibit pyroptosis, and enhance antioxidant defense mechanisms. Hybrid systems—including nanoparticles and hydrogels—enable targeted delivery and prolonged action, thereby stimulating regeneration and angiogenesis. Thiol-activated donors (e.g., COS/H₂S and AlaCOS) allow controlled H₂S release, offering broad opportunities for precise modulation of its concentration within target tissues. Inhibitors (e.g., AOAA, PAG, oxamic hydrazide 1, L-aspartic acid, benserazide, and NSC4056) of H₂S biosynthesis underscore the physiological importance of this gasotransmitter, as their administration enhances neuroinflammation and diminishes neuroprotection. The analysis reveals a general pattern: all classes of H₂S donors effectively modulate key pathological mechanisms, differing in their rate, duration, and specificity of action. These findings highlight the therapeutic promise of H₂S-based pharmacological agents in clinical neurotraumatology, while emphasizing the need for further research to optimize delivery systems, enhance efficacy, and minimize adverse effects. Full article

Phenylene-based bis-oxamate polydentate ligands offer a unique opportunity for creating a large variety of coordination compounds, in which paramagnetic metal ions are strongly magnetically coupled. The employment of imino nitroxyl (IN) radicals as supplementary ligands confers numerous benefits, including the strong ferromagnetic interaction between Ni and IN. Furthermore, the chelating IN can act as a capping ligand, thereby impeding the formation of coordination polymers. In this study, we present the molecular and crystal structure and experimental and theoretical magnetic behavior of an exceptional neutral trinuclear complex [Ni(L³⁻)₂(IN)₃]∙5CH₃OH (1) (L is N,N′-1,3-phenylenebis-oxamic acid; IN is [4,4,5,5-tetramethyl-2-(6-methylpyridin-2-yl)-4,5-dihydro-1H-imidazol-1-yl]oxidanyl radical) with a cyclic triangular arrangement. Moreover, in this compound three Ni²⁺ ions are linked by the two bis-oxamate ligands playing a rare tritopic function due to an unprecedented triple deprotonation of the related meta-phenylene-bis(oxamic acid). The main evidence of such a deprotonation of the ligand is the neutrality of the cluster, since there are no anions or cations compensating for its charge in the crystals of the compound. Despite the presence of six possible magnetic couplings in the trinuclear cluster 1, its behavior was reproduced with a high degree of accuracy using a three-J model and ZFS, under the assumption that the three different Ni-IN interactions are equal to each other, whereas only two equivalent-in-value Ni-Ni interactions were taken into account, with the third one being equated to zero. Our study indicates the presence of two opposite-in-nature types of magnetic interactions within the triangular core. DFT and CASSCF/NEVPT2 calculations were completed to support the experimental magnetic data simulation. Full article

Enhancement of glycolysis has been reported in tumor cells, and it is believed that this enhancement is important for maintaining the stemness of tumor cells and contributes to malignant phenotypes. Here, we investigated the effects of Oxamate, which inhibits glycolysis by blocking the conversion of pyruvate to lactate, on radiosensitivity and its molecular mechanisms in T98G glioblastoma cells. Oxamate significantly enhanced radiosensitivity by delaying DNA repair, as indicated by the persistence of γ-H2AX foci up to four days post-irradiation. Mechanistically, Oxamate suppressed the expression and phosphorylation of key DNA repair factors. Furthermore, Oxamate induced apoptosis and promoted cellular senescence, as evidenced by the accumulation of SA-β-gal and the upregulation of pS15-p53 and p21. In addition, Oxamate downregulated EGFR expression, reduced the levels of stem cell markers, and modulated epithelial–mesenchymal transition (EMT) markers, suggesting a potential suppression of EMT-related pathways. Together, these results demonstrate that Oxamate enhances radiosensitivity in glioblastoma cells through multiple mechanisms, including the inhibition of DNA repair, induction of apoptosis and senescence, and suppression of cancer stem cell properties and EMT. Our findings provide new insights into the potential use of Oxamate as a radiosensitizer and warrant further investigation of its clinical application in glioblastoma therapy. Full article

Herein, we present the synthesis and characterization of a series of isostructural lanthanide(III) compounds with the N-(4-carboxyphenyl)oxamic acid (H₃pcpa) ligand of the general formula as {[Ln₂(Hpcpa)₃(H₂O)₅]}_n [Ln = Dy(III) 1, Ho(III) 2, Er(III) 3]. The structure of 3 consists of neutral zig–zag chains of Er(III) ions, with Hpcpa^2– ligands acting as bridges in a bidentate/monodentate coordination mode with five water molecules achieving the eight-coordination around the two Er(III) ions within the repeating bis(carboxylate)-bridged dinuclear units along the chain. The magnetic and magnetocaloric properties were studied for 1–3. Compound 1 presents a field-induced slow relaxation of the magnetization with a “reciprocating thermal behavior” below 5 K for H = 0.25 T, while 2 shows maxima of the magnetic entropy from 3 up to 6 K for ΔH > 2 T. Full article

Background/Objectives: Natural cytokinins are a promising group of anti-tumor agents. In this work, we hypothesized that modification of the ethylenediurea moiety with alkyl and oxygen-containing groups could be a way to enhance the anti-proliferative properties of the molecule. Methods: Ten new analogs of ethylenediurea with these substitutions were tested for anti-proliferative activity in the human cancer cell lines MDA-MB-231 (breast cancer), A-375 (melanoma), and U-87 MG (glioblastoma) during 72 h of incubation using resazurin test and evaluated the substances receptor using molecular docking. Results: The compound with the carbamate link and ethylene substituent on the phenyl ring inhibited proliferation in these models by 70–90% without cytotoxic effects. The compound did not affect the viability of the immortalized fibroblast cell line Bj-5ta. The compound was also able to enhance the action of doxorubicin and temozolomide by about 20%. According to the molecular modeling data, the probable receptor target for the synthesized compound was the A2AR adenosine receptor. Conclusions: The results obtained on the ethylenediurea analogs with ethyl substituent in the aromatic ring are promising for the development of novel anticancer therapeutics. Full article

This laudatio is dedicated to Professors Miguel Julve Olcina and Francisco Lloret Pastor on the occasion of their retirement in 2024. The first part deals with the scientific trajectory of the Coordination Chemistry team at the University of Valencia, within the Department of Inorganic Chemistry on the Burjassot campus and then in the Paterna Institute of Molecular Science. The second part relates some of the more salient results of the heritage left by our two colleagues in molecular magnetism, where they developed, in their own way, a rational approach to designing, creating and understanding a wealth of brand new systems from the simplest to Multifunctional Molecule-based Magnetic Materials. The robust and friendly links between our two colleagues are emphasized in the third part. Full article

Background/Objectives: The avascular nature of the follicle creates a hypoxic microenvironment, establishing a niche where granulosa cells (GCs) rely on glycolysis to produce energy in the form of lactate (L-lactate). Autophagy, an evolutionarily conserved stress-response process, involves the formation of autophagosomes to encapsulate intracellular components, delivering them to lysosomes for degradation. This process plays a critical role in maintaining optimal follicular development. However, whether hypoxia regulates autophagy in GCs via lactate remains unclear. Methods: In this study, we investigated lactate-induced autophagy under hypoxia by utilizing glycolysis inhibitors or silencing related genes. Results: We observed a significant increase in autophagy in ovarian GCs under hypoxic conditions, indicated by elevated LC3II levels and reduced P62 levels. Suppressing lactate production through glycolytic inhibitors (2-DG and oxamate) or silencing lactate dehydrogenase (LDHA/LDHB) effectively reduced hypoxia-induced autophagy. Further investigation revealed that the HIF1-α/BNIP3/Beclin-1 axis is essential for lactate-induced autophagy under hypoxic conditions. Inhibiting HIF-1α activity using siRNAs or PX-478 downregulated BNIP3 expression and subsequently suppressed autophagy. Similarly, BNIP3 silencing with siRNAs repressed lactate-induced autophagy in hypoxic conditions. Mechanistically, immunoprecipitation experiments showed that BNIP3 disrupted pre-existing Bcl-2/Beclin-1 complexes by competing with Bcl-2 to form Bcl-2/BNIP3 complexes. This interaction released Beclin-1, which subsequently triggered lactate-induced autophagy under hypoxic conditions. Conclusions: These findings unveil a novel mechanism by which hypoxia regulates GC autophagy through lactate production, highlighting its potential role in sustaining follicular development under hypoxic conditions. Full article

In this work, we describe the synthesis, crystal structures and magnetic properties of four air-stable mononuclear lanthanide(III) complexes with the N-(2,4,6-trimethylphenyl)oxamate (Htmpa) of formula: n-Bu₄N[Nd(Htmpa)₄(H₂O)]·4H₂O (1), n-Bu₄N[Gd(Htmpa)₄(H₂O)]·3DMSO·2H₂O (2), n-Bu₄N[Tb(Htmpa)₄(H₂O)]·3DMSO·1H₂O (3) and n-Bu₄N[Dy(Htmpa)₄(H₂O)]·3DMSO·2H₂O (4) (n-Bu₄N⁺ = n-tetrabutylammonium; DMSO = dimethylsulfoxide). Their crystal structures reveal the occurrence of calixarene-type monoanionic species containing all-cis-disposed Htmpa ligands and one water molecule coordinated with the respective Ln^III ion (Ln = Nd, Gd, Tb and Dy), featuring a nine-coordinated environment with muffin (MFF-9) (1) or spherical-capped square antiprism (CSAPR-9) (2–4) geometry. The major difference between their crystal structures is related to the nature of crystallization solvent molecules, either water (1) or both DMSO and water (2–4). The intermolecular hydrogen bonds among the self-complementary Htmpa ligands in all four compounds mediated a 2 D supramolecular network in the solid state. Direct-current (dc) magnetic properties for 1–4 show typical behavior for the ground state terms of the Ln^III ions [⁴I_9/2 (Nd); ⁸S_7/2(Gd), ⁷F₆ (Tb), ⁶H^15/2 (Dy)]. Alternating-current (ac) magnetic measurements reveal the presence of slow magnetic relaxation without the presence of a dc field only for 4. In contrast, field-induced slow magnetic relaxation behavior was found in complexes 1, 2 and 3. Full article

The synthesis, structural, and magnetic characterization of a novel neutral copper(II) hexanuclear complex [Cu₆(en)₄(OCH₂CH₂O)₂(pyox)₄]·3eg·en·12H₂O (1) was investigated [en = ethylenediamine, eg = ethylene glycol, and H₂pyox = 4-(1H-pyrazole-4-yl)phenylene-N-oxamic acid]. The crystal structure of 1, obtained by the single-crystal X-ray diffraction technique, revealed that the hexacopper(II) complex is built from two linear tricopper(II) complex subunits. Each subunit contains two [Cu(en)]²⁺ moieties connected to a [Cu(OCH₂CH₂O)] unit by two pyox²⁻ ligands acting as μ-κN:κN′ bridges, as well as a [OCH₂CH₂O]²⁻ ligand, which is ultimately found in the μ₃-κO,O′:κO:κO′ coordination form. The subunits are connected via the amide portion of the pyox²⁻ ligand, linked to copper atoms in the other subunit. They occupy the apical coordination positions, leading the trinuclear copper(II) segments to be almost perpendicular. The structural, chemical, and spectroscopic characterizations evidenced that ethylene glycol acted both as a solvent and a reactant upon deprotonation, forming the –OCH₂CH₂O– ligand due to the basic crystallization environment. DC magnetic studies revealed a strong antiferromagnetic interaction between the copper atoms within the trinuclear subunits, influenced by alkoxide and pyrazolate bridging ligands. Our findings offer new insights into the structural and magnetic properties of copper(II) complexes, enhancing the understanding of metal–ligand interactions in supramolecular chemistry. Full article

The use of tris(4-aminophenyl)amine (TAPA) as central to the synthesis of both polyimines and polyimides and covalent organic frameworks and inorganic cages, among others, has grown in the last few years. The resulting materials exhibit high performance in their area of application. In this contribution, the crystal structures of two TAPA derivatives, triethyl (nitrilotris(benzene-4,1-diyl))tricarbamate (1) and triethyl 2,2′,2″-((nitrilotris(benzene-4,1-diyl))tris(azanediyl))tris(2-oxoacetate) (2), are described. The molecular and supramolecular structures of both compounds were compared between them and with analogous compounds. The analyses of their vibrational and ¹³C-CPMAS NMR spectroscopies, as well as their thermal stability, were included and corelated with the crystal structure. Hirshfeld surface analysis on the crystal structures of both TAPA derivatives revealed the stabilization of the crystal network via the amide N—H∙∙∙O interactions of dispersive nature in the carbamate, whereas dispersive carbonyl–carbonyl interactions also played a competitive role in the supramolecular arrangement of the oxamate. Interaction energy DFT calculations performed at the B3LYP/6-31G(d,p) level allowed us to estimate the energy contributions and nature of several interactions in terms of the stability of both crystal lattices. Full article

Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon’s antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy. Full article

Limited substrate availability because of the blood–brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity, primary cortical cells were incubated in glucose- or lactate-containing media and toxic concentrations of glutamate for 24 h. Cell death was determined by immunostaining and lactate dehydrogenase (LDH) release. Mitochondrial membrane potential and nitric oxide (NO) levels were measured using Tetramethylrhodamine, methyl ester (TMRM) and 4-Amino-5-Methylamino-2′,7′-Difluorofluorescein Diacetate (DAF-FM) live staining, respectively. LDH activity was quantified in single cells in the presence of lactate (LDH substrate) and oxamate (LDH inhibitor). Nuclei of cells were stained with DAPI and neurons with MAP2. Based on the distance between neurons and glial cells, they were classified as linked (<10 µm) and non-linked (>10 µm) neurons. Lactate increased cell death rate and the mean value of endogenous NO levels compared to glucose incubations. Mitochondrial membrane potential was lower in the cells cultured with lactate, but this effect was reversed when glutamate was added to the lactate medium. LDH activity was higher in linked neurons compared to non-linked neurons, supporting the hypothesis of the existence of the lactate shuttle between astrocytes and at least a portion of neurons. In conclusion, glucose or lactate can equally preserve primary cortical neurons, but those neurons having a low level of LDH activity and incubated with lactate cannot cover high energetic demand solely with lactate and become more susceptible to glutamate toxicity. Full article