Search Results (511)

Depression is a prevalent psychiatric disorder in which oxidative stress and nitric oxide (NO) signaling have been implicated. Natural compounds such as Punica granatum have shown potential antidepressant effects, but their mechanisms remain unclear. This study aimed to evaluate the antidepressant-like effects of an aqueous extract of P. granatum in male Swiss Webster mice and to explore the possible involvement of NO-related system. Acute administration of P. granatum (0.25–2 mg/kg, i.p.) was tested in the forced swim and tail suspension tests. The interaction with NO signaling was examined through co-administration with an NO donor (sodium nitroprusside, SNP) and NOS inhibitors (NG-nitro-L-arginine methyl ester, L-NAME and 7-nitroindazole, 7-NI). Biochemical markers of oxidative stress (lipid peroxidation and GSH/GSSG ratio) were also assessed. P. granatum significantly reduced immobility and increased swimming behavior, consistent with an antidepressant-like effect. SNP, L-NAME, and 7-NI induced pro-depressant effects, which were prevented by P. granatum co-administration. Treatment also attenuated oxidative stress markers in the hippocampus and prefrontal cortex. These findings suggest that the antidepressant-like effects of P. granatum may involve interactions with NO signaling, although this interpretation remains indirect, as specific NO pathway indices were not measured. Acute P. granatum administration exerts antidepressant-like and antioxidant effects in male mice. The results support its potential as a natural candidate for depression treatment, particularly in conditions associated with oxidative imbalance and possible NO dysregulation. Future studies should confirm these mechanisms using direct molecular assessments and include female cohorts. Full article

Background: Chagas disease poses a significant public health challenge, particularly impacting socioeconomically vulnerable populations. Current treatment strategies still rely on two nitro heterocyclic compounds: benznidazole and nifurtimox. Both agents exhibit limited therapeutic efficacy during the chronic phase of the disease and are often linked to severe adverse effects that frequently lead to treatment discontinuation. This urgent need for safer, more effective oral treatments drives the development of novel chemotypes. Objective: In this study, we advanced the preclinical evaluation of 4-imidazoline-1H-pyrazole derivatives, which have been identified as promising candidates against Trypanosoma cruzi. Methods: The candidate compound identified from the reversibility assay underwent further evaluation for its efficacy using a three-dimensional (3D) culture model and a Transwell co-culture system, in addition to the in vivo assessment. Results: Our findings revealed that compound 3m (3-Cl, 4-CH₃) exhibited low cytotoxicity while substantially decreasing the parasite burden in 3Dcardiac spheroid models. The compound effectively permeated Caco-2 cell monolayers and demonstrated the ability to inhibit T. cruzi infection in Vero cell cultures within a co-culture system. Furthermore, the 3m derivative not only controlled parasite resurgence but also showed significant therapeutic benefits in a murine model of acute T. cruzi infection, resulting in marked reductions in parasitemia and tissue parasitism, associated with diminished inflammatory infiltrate and cardiac fibrosis. Treatment with 3m increased the survival rate of infected mice to 40%, comparable to the reference drug benznidazole in several key pathological endpoints. Conclusion: These findings highlight the potential of 4-imidazoline-1H-pyrazole derivatives, particularly compound 3m, in mitigating the pathological effects associated with T. cruzi infection. Full article

Background/Objectives: Neurological and psychiatric disorders share overlapping mechanisms, such as oxidative stress, neuroinflammation, and neurotransmitter imbalance. In this context, multitarget natural molecules have gained attention. 1-nitro-2-phenylethane (1N2PE), a major constituent of Aniba canelilla essential oil, is known for its antioxidant, anti-inflammatory, and anticholinesterase effects, yet its neuropharmacological profile remains poorly understood. Methods: This study integrated in silico predictions and in vivo behavioral assays to characterize 1N2PE. Results: Pharmacokinetic analyses indicated favorable drug-like properties, with high gastrointestinal absorption, blood–brain barrier penetration, and no P-gp substrate profile. Molecular docking and dynamics revealed stable interactions with dopamine transporter (DAT, ΔG = −26.26 kcal/mol), prostaglandin-H synthase-1 (PGHS-1, ΔG = −20.27 kcal/mol), serotonin transporter (SERT, ΔG = −18.20 kcal/mol), and acetylcholinesterase (AChE, ΔG = −16.58 kcal/mol). In vivo, using a scopolamine-induced impairment model, 1N2PE significantly improved spatial memory and cognition in the Morris water maze. Treated animals reduced the distance to the target zone by ~40% compared with scopolamine-only rats (p < 0.01), normalized latency during training, and exhibited 30% less immobility (p < 0.05), indicating antidepressant-like effects. Moreover, 1N2PE attenuated anxiety-like thigmotaxis, restoring exploratory patterns (p < 0.0001). Conclusions: Together, these findings highlight 1N2PE as a multitarget candidate for cognitive and psychiatric disorders, combining favorable pharmacokinetic properties with preclinical efficacy, warranting further biochemical and translational investigations. Full article

Background/Objectives: The rapid progression of stroke often results in irreversible brain damage and poor outcomes when treatment is delayed. Prophylactic administration of FAD012 (3,5-dimethyl-4-hydroxycinnamic acid), a synthetic derivative of ferulic acid (FA), has demonstrated cerebroprotective effects in ischemic models through antioxidant and endothelial protective mechanisms. This study investigated the effects of FAD012 on cerebral infarction and blood–brain barrier (BBB) integrity using a photothrombotic stroke model in rats. Methods: Male Sprague Dawley rats received a single intraperitoneal injection of FAD012 or FA (100 or 300 mg/kg) 60 min prior to stroke induction. Under isoflurane anesthesia, the middle cerebral artery was exposed, and stroke was induced by intravenous administration of Rose Bengal followed by green laser irradiation. Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry. BBB disruption was evaluated by Evans Blue extravasation and immunohistochemistry for tight junction (TJ) proteins. Results: Control rats exhibited extensive infarction, BBB disruption, and reduced expression of claudin-5, occludin, and ZO-1, along with fragmented collagen IV. In contrast, FAD012 (300 mg/kg) significantly attenuated CBF reduction, reduced infarct size, preserved BBB integrity, and maintained TJ protein expression, with greater efficacy than an equivalent dose of FA. FAD012 also preserved the expression and phosphorylation of endothelial nitric oxide synthase (eNOS), a key marker of vascular integrity. The CBF-preserving effect of FAD012 was completely abolished by N^G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Conclusions: These findings suggest that FAD012 protects endothelial function, thereby contributing to the maintenance of CBF and BBB integrity, supporting its potential as a prophylactic therapeutic agent for ischemic stroke. Full article

Introduction: 5-HMF is a molecule found in carbohydrate-rich foods that is associated not only with cancer and anaphylactic reactions, but also with anti-oxidant properties. Questions arose as to whether 5-HMF exhibited a catalytic effect in relation to lipid peroxidation and lipoprotein oxidation in presence of metals and/or radicals. Methods: Peroxynitrite (ONOO⁻)-induced chemiluminescence and ONOO⁻ nitration of tyrosine residues on BSA using anti-nitro-tyrosine-antibodies were used to measure the protection of 5-HMF against peroxides or nitration compared to vitamin C (VitC). The reductive potential of 5-HMF or VitC on Cu²⁺ or Fe³ was estimated using the bicinchoninic acid (BCA) or Fenton-complex method. Human plasma was used to measure the generation of malondialdehyde (MDA), 4-hydroxynonenal (HNE), and total thiols after Fe²⁺/H₂O₂ oxidation in the presence of different concentrations of 5-HMF or VitC. Finally, Cu²⁺ oxidation of LDL after 4 h was carried out with 5-HMF or VitC, measuring the concentration of MDA in LDL with the thiobarbituric assay (TBARS). Results: VitC was 4-fold more effective than 5-HMF in scavenging ONOO⁻ to nearly 91.5% at 4 mM, with the exception of 0.16 mM, where the reduction of ONOO⁻ by VitC was 3.3-fold weaker compared to 0.16 mM 5-HMF. VitC or 5-HMF at a concentration of 6 mM inhibited the nitration of tyrosine residues on BSA to nearly 90% with a similar course. While 5-HMF reduced free Fe³⁺ in presence of phenanthroline, forming Fe²⁺ (phenantroleine)₃ [Fe²⁺(phe)₃] or complexed Cu²⁺(BCA)₄ to Cu⁺(BCA)₄ weakly, VitC was 7- to 19-fold effective in doing so over all the used concentrations (0–25 mM). A Fe²⁺—H₂O₂ solution mixed with human plasma showed a 6–10 times higher optical density (OD) of MDA or HNE in the presence of 5-HMF compared to VitC. The level of thiols was significantly decreased in the presence of higher VitC levels (1 mM: 198.4 ± 7.7 µM; 2 mM: 160.0 ± 13.4 µM) compared to equal 5-HMF amounts (2562 ± 7.8 µM or 242.4 ± 2.5 µM), whereas the usage of lower levels at 0.25 µM 5-HMF resulted in a significant decrease in thiols (272.4 ± 4.0 µM) compared to VitC (312.3 ± 19.7 µM). Both VitC and 5-HMF accelerated copper-mediated oxidation of LDL equally: while the TBARS levels from 4 h oxidized LDL reached 137.7 ± 12.3 nmol/mg, it was 1.7-fold higher using 6 mM VitC (259.9 ± 10.4 nmol/mg) or 6 mM 5-HMF (239.3 ± 10.2 nmol/mg). Conclusions: 5-HMF appeared to have more pro-oxidative potential compared to VitC by causing lipid peroxidation as well as protein oxidation. Full article

The extensive use of submicron emulsion systems, particularly those stabilized by nonionic surfactants, with their proven effectiveness and safety profile, provides a reassuring foundation for our research. Consequently, we designed and engineered new submicron emulsion formulations stabilized with a biocompatible surfactant polyoxyethylated cocoamine, whose nonionic character is due to a high degree of polyoxyethylation. We chose oleic acid as the oil phase, a fatty acid known for its beneficial properties. This led to novel biocompatible nanoemulsions with high stability and cosurfactant-free microemulsions. The dynamic light scattering studies confirmed that both formulations have a nanometric size and low polydispersity index values. Moreover, transmission electron microscopy verified the nanodroplets’ morphological homogeneity and spherical shape. The resulting nanoplatforms can be applied to carry bioactive agents in the pharmaceutical and cosmetic fields. For this reason, we solubilized newly synthesized 5-dimethylamino-5′-nitro-2,2′-bithiophene as a model hydrophobic cargo for delivering poorly water-soluble compounds. This dye was chosen due to its strong solvatochromic behavior and suitability for micropolarity analysis via UV–Vis spectroscopy. We also present a simple method for rapid micropolarity screening to assess the type of nanodispersion via solvatochromic shift as an alternative procedure for evaluating of the oils used to fabricate nanoformulations for pharmaceutical and cosmetic purposes. Full article

Nitric esters are among the compounds that can liberate nitrogen monoxide (NO) in the organism. Due to the vasodilatation caused by nitrogen monoxide, NO-donors have been shown to protect endothelial function, acting as vasodilators, promoting efficient oxygen supply to tissues, to lower blood pressure, and to inhibit platelet aggregation. Incorporation of a NO-liberating moiety in the structure of non-steroidal anti-inflammatory drugs results in anti-inflammatory agents that are safer for the gastrointestinal system. In this research, ibuprofen and naproxen, two commonly applied non-steroidal anti-inflammatory drugs (NSAID), non-selective inhibitors of cyclooxygenases, were used to design novel anti-inflammatory agents able to release NO in the organism. Thus, the NSAIDs were amidated with beta-alanine and L-proline, which were able to incorporate the 2-nitro-oxyethyl moiety as the NO donor. The resulting compounds were anti-inflammatory agents, found to be more potent than the mother drugs, demonstrating remarkable inhibition of cyclooxygenase-2 over cyclooxygenase-1 and the ability to release NO in vitro. Furthermore, two of the most active anti-inflammatory compounds proved to be effective hypolipidemic agents, decreasing plasma total cholesterol, triglycerides, and LDL-cholesterol in hyperlipidemic rats significantly. The most effective compound in all the above tests was the ibuprofen derivative 5, which inhibited COX-2 by 95%, decreased inflammation by 73%, and reduced all lipidemic indices by more than 50%. Furthermore, docking experiments of compound 5 on the active sites of COX-1 and COX-2 showed that it interacts intensely with the binding site of COX-2, and the binding energy is equivalent to that of the relevant to celecoxib selective COX-2 inhibitor 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide (SC-5580). In conclusion, the performed structural modifications resulted not only in the improvement of the anti-inflammatory activity, compared with the parent NSAID, but also acquired strong hypolipidemic activity. Thus, the combination of structural characteristics resulting in a decrease in lipidemia, with possible inhibition of atherosclerosis, due to their anti-inflammatory activity and vasodilatation ability, via the liberated NO, may constitute a useful rationale for new compounds. Full article

Biochars were prepared from rice husk at different pyrolysis temperatures (300, 400, and 500 °C) and then modified by nitric acid (HNO₃) and potassium hydroxide (KOH). The chemical and physical properties were characterized, and the adsorption ability of biochars for the removal of Cd (II) and Pb (II) was investigated. The results showed that with increasing pyrolysis temperature, the aromaticity of rice husk biochar increased while its polarity decreased and both specific surface area and total pore volume significantly increased. Both HNO₃ and KOH modification significantly changed the oxygen-containing functional groups in biochar, especially biochars prepared at lower pyrolysis temperatures. HNO₃ modification introduced nitro and carboxyl groups on the surface of HNO₃-BC300, increasing the ether bond functional groups, while KOH modification increased the content of hydroxyl groups on KOH-BC300 and reduced the ether bond groups. At the same time, the modification of rice husk-derived biochar greatly enhanced the ability to absorb Cd (II) and Pb (II) from aqueous solution. Notably, KOH-BC300 exhibited the highest adsorption capacities, reaching 72.14 mg·g⁻¹ for Cd (II) and 170.84 mg·g⁻¹ for Pb (II). These results demonstrate that KOH modification was more effective than HNO₃ modification at enhancing the adsorption of Cd (II) and Pb (II) onto rice husk-derived biochar. In addition, the specific surface area and total pore volume of biochar increased significantly after HNO₃ and KOH modification. It was concluded that biochar’s adsorption performance might be greatly improved by increasing its oxygen-containing functional groups and specific surface area, but the effect of oxygen-containing functional groups was greater than that of specific surface area. Thus, KOH-modified biochar (KOH-BC300) can be used as an effective sorbent for heavy metal removal from wastewater. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, limiting the efficacy of conventional targeted therapies. As a result, novel therapeutic strategies are urgently needed. Photodynamic therapy (PDT), which relies on the activation of photosensitizers (PSs) by light to induce cytotoxic effects, has emerged as a promising alternative for TNBC treatment. Furthermore, the conjugation of PSs with targeting peptides has demonstrated enhanced selectivity and therapeutic efficacy, particularly for porphyrin-based photosensitizers. In this study, we report the synthesis of novel porphyrin–peptide conjugates designed to selectively target the epidermal growth factor receptor (EGFR), which is frequently overexpressed in TNBC. The conjugates were prepared via thiol displacement of the meso-nitro group in a 5,15-diarylporphyrin scaffold using EGFR-binding peptides. Photodynamic activity was evaluated in two EGFR-overexpressing TNBC cell lines. Cellular uptake of the conjugates correlated with EGFR expression levels, and PDT treatment resulted in differential induction of necrosis, apoptosis, and autophagy. Notably, the conjugates significantly inhibited EGFR-expressing cell line migration, a critical hallmark of metastatic progression. These findings underscore the potential of EGFR-targeted porphyrin–peptide conjugates as promising PDT agents for the treatment of TNBC. Full article

Increased drug metabolism and elimination are prominent mechanisms mediating multidrug resistance (MDR) to not only chemotherapy drugs but also anti-cancer natural products, such as benzyl isothiocyanate (BITC). To evaluate the possibility of combined utilization of a certain compound to overcome this resistance, we focused on glutathione S-transferase (GST)-dependent metabolism of BITC. The pharmacological treatment of a pi-class GST-selective inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), significantly increased BITC-induced toxicity in human colorectal cancer HCT-116 cells. However, NBDHEX unexpectedly increased the level of the BITC–glutathione (GSH) conjugate as well as BITC-modified proteins, suggesting that NBDHEX might increase BITC-modified protein accumulation by inhibiting BITC–GSH excretion instead of inhibiting GST. Furthermore, NBDHEX significantly potentiated BITC-induced apoptosis with the enhanced activation of apoptosis-related pathways, such as c-Jun N-terminal kinase and caspase-3 pathways. These results suggested that combination treatment with NBDHEX may be an effective way to overcome MDR with drug efflux and thus induce the biological activity of BITC at lower doses. Full article

N′-Phenylbenzohydrazides are valuable precursors for air- and moisture-stable Blatter radicals, with applications in magnetism and spintronics. This study presents the single-crystal X-ray structures of N′-(4-methyl-2-nitrophenyl)benzohydrazide (I) and N′-(2-nitro-(4-trifluoromethyl)phenyl)benzohydrazide (II), highlighting the influence of substituents on supramolecular arrangement. Compounds I and II are found to crystallize within the monoclinic crystal system, with the space groups I2/a and P2₁/n, respectively, with centrosymmetric, one-dimensional columnar packing driven by π-π stacking. In I, π-π dimers form between benzoyl rings (3.018 Å), with additional stacking between aryls (3.408 Å) of neighboring dimers. In II, alternating benzoyl and aryl rings stack with interplanar distances of 2.681 and 2.713 Å. Bifurcated intra- and intermolecular hydrogen bonds (1.938–2.478 Å) further stabilize the packing. Compound II exhibits inter-stack F···F contacts (2.924 Å), attributed to steric effects. The trifluoromethyl group enhances N′NCO-NO₂ conjugation, resulting in a near-parallel arrangement of aromatic rings and planar geometry at the N′ nitrogen. In contrast, compound I shows reduced conjugation, leading to pyramidalization at the N′ nitrogen and increased hydrazide bond flexibility, as seen in the 56° angle between aromatic rings. Full article

Aryl diazonium salt chemistry offers a robust and versatile approach for the modification of material surfaces via the covalent immobilization of reactive functional groups under mild conditions. In this study, this strategy was successfully applied to graft the chelating agent 4-(2-pyridylazo)resorcinol (PAR) onto Amberlite XAD-4 resin. Initially, 4-nitrobenzenediazonium tetrafluoroborate (NBDT) was covalently anchored onto the resin surface using hypophosphorous acid as a reducing catalyst to introduce aryl nitro groups. These nitro groups were subsequently reduced to aniline functionalities, enabling diazo coupling with PAR. The successful modification of the resin was confirmed by ATR-FTIR spectroscopy, thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). The synthesized chelating resin exhibited sorption capacities of 0.152, 0.167, and 0.172 mM g⁻¹ for Co(II), Ni(II), and Cu(II), respectively. The functionalized resin was packed into standard SPE cartridges and employed as a selective sorbent for the extraction and preconcentration of trace metals from groundwater samples collected from Dhalamah Valley, Al-Madinah Al-Munawwarah, prior to quantification by inductively coupled plasma mass spectrometry (ICP-MS). These results demonstrate the effectiveness of rapid diazonium-based surface functionalization for the preparation of selective polymeric metal chelators suitable for the extraction of trace metals from complex groundwater matrices. Full article

Background and Objectives: Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by cholinergic deficits, oxidative stress, amyloid-β (Aβ) aggregation, and tau hyperphosphorylation. Caffeic acid (CA), a naturally occurring hydroxycinnamic acid, has emerged as a promising neuroprotective candidate due to its antioxidant, anti-inflammatory, and enzyme-inhibitory properties. This review systematically evaluates recent in vitro and in vivo evidence regarding the therapeutic potential of CA in AD models and examines the impact of delivery systems and derivatives on its efficacy and bioavailability. Materials and Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases, adhering to the PRISMA 2020 guidelines. Studies published between January 2021 and April 2025 were included in this review. Eligible studies investigated the effects of CA or CA-enriched extracts on AD-relevant mechanisms using in vitro, in vivo, and in silico models. After screening 101 articles, 44 met the inclusion criteria and were included in the final qualitative synthesis of the study. Results: In vitro studies have confirmed that CA modulates cholinergic activity by inhibiting AChE and BChE and exerting antioxidant and anti-amyloidogenic effects. In vivo studies using pharmacological, genetic, and metabolic AD models have demonstrated improvements in cognitive function, reduction in oxidative stress, inflammation, and Aβ and tau pathologies following CA administration. Advanced delivery platforms, such as solid lipid nanoparticles, transferrin-functionalized liposomes, and carbon dot systems, have significantly enhanced CA’s brain bioavailability and therapeutic efficacy. CA derivatives, including caffeic acid phenethyl ester and nitro-substituted analogs, exhibit improved pharmacokinetic and neuroprotective profiles. Conclusions: This review provides evidence supporting the use of CA as a promising multitarget agent against AD pathology. Its therapeutic potential is further enhanced by nanotechnology-based delivery systems and chemical modifications that overcome the limitations of bioavailability. Continued preclinical evaluation and translational studies are warranted to support its clinical development as an AD intervention. Full article

Background/Objectives: Nelumbo nucifera Gaertn. (lotus) seeds have traditionally been used to treat hypertension, though their mechanisms remain unclear. This study investigated the antihypertensive effects of lotus seed extract (LSE) and its mechanisms in rats with N^ω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Methods: Male Sprague Dawley rats received L-NAME (40 mg/kg/day) in drinking water and were treated orally with LSE (5, 10, or 100 mg/kg/day), captopril (5 mg/kg/day), or a combination of LSE and captopril (2.5 mg/kg/day each) for 5 weeks. Hemodynamic parameters and histological changes in the left ventricle and aorta were assessed. Mechanistic studies included measurements of plasma nitric oxide (NO) metabolites, malondialdehyde (MDA), superoxide dismutase (SOD) activity, angiotensin II (Ang II), angiotensin-converting enzyme (ACE) activity, and protein expression via western blot. Results: L-NAME elevated systolic blood pressure and induced cardiovascular remodeling, oxidative stress, and renin-angiotensin system activation. LSE treatment reduced blood pressure, improved antioxidant status, increased NO bioavailability, and downregulated gp91^phox and AT₁R expression. The combination of low-dose LSE and captopril produced stronger effects than LSE alone, with efficacy comparable to captopril. Conclusions: These findings suggest that LSE exerts antihypertensive effects via antioxidant activity and inhibition of the renin-angiotensin system, supporting its potential as an adjunct therapy for hypertension. Full article

The dissociation of the C-NO₂ bond is the initial step in the process of the detonation of nitroaromatic explosives. The strength of the C-NO₂ bond is significantly influenced by the relative position of the nitro group with respect to the aromatic ring plane since the planar arrangement enables the delocalization of electron density, which strengthens this bond. In this study, we have combined a statistical analysis of geometrical parameters extracted from crystal structures of trinitroaromatic molecules with ab initio calculations of non-covalent index plots and Wiberg bond index values for selected trinitroaromatic molecules to elucidate the influence of nearby substituents on the relative position of nitro groups with respect to the aromatic ring plane. The results of the analysis showed that neighboring substituents have a significant impact on the geometry of nitro groups. The results also showed that this influence arises from the repulsive interaction of voluminous substituents, attractive non-covalent contacts, and the electronic effects of substituents. Full article