Search Results (987)

Pancreatic ductal adenocarcinoma (PDAC) has limited effective therapeutic strategies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and may affect tumor cell fitness via the mevalonate pathway, mitochondrial function, and redox homeostasis. We systematically compared seven statins in patient-derived PDAC cell lines and related viability effects to mitochondrial, redox, cell-cycle, apoptotic, and metabolic responses. Statins were tested in three PDAC cell lines (PDAC-1/2/3) using MTT assays (5–20 µM; 24–120 h). Based on MTT responses, mechanistic profiling was performed after 72 h at 20 µM concentration using lipophilic statins, including apoptosis (Annexin V/7-AAD), cell-cycle distribution, mitochondrial membrane potential (Δψm), intracellular ROS, and ¹H-NMR quantification of intracellular and extracellular metabolites. Statins reduced viability in a concentration- and time-dependent manner, with lipophilic statins more active than hydrophilic. PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 comparatively resistant. PDAC-1 and PDAC-3 showed G0/G1 accumulation, Δψm depolarization, reactive oxygen species (ROS) elevation, and Annexin V–positive apoptosis, whereas PDAC-2 (high basal ROS) showed ROS reduction and limited apoptosis despite Δψm loss. Metabolomics indicated reduced glucose and amino-acid utilization and lactate secretion while preserving line-specific metabolic fingerprints. PDAC cell lines display marked inter-tumoral heterogeneity in statin responses, supporting evaluation of statins as chemosensitizing adjuvants in functionally guided PDAC treatment strategies. Full article

The development of sustainable and environmentally benign N-methylation methodologies is essential for enhancing sustainable synthetic practice in pharmaceutical manufacturing. In this study, we demonstrate that microwave heating (MWH) markedly enhanced the efficiency of cobalt-catalyzed N-methylation using methanol or methanol-d₄ as green C1 sources. Compared with conventional heating (CH), MWH enabled highly efficient syntheses of key pharmaceutical intermediates—including 6-dimethylamino-1-hexanol, imipramine hydrochloride, and butenafine hydrochloride—under milder conditions and shorter reaction times and without generating hazardous halogen-containing waste. UV–vis spectroscopic analysis revealed that MWH accelerated the transformation of Co(acac)₂ into catalytically active Co species by approximately four-fold, providing a mechanistic basis for the enhanced reactivity. We hypothesized that this effect was caused by the selective microwave heating of the catalyst, which in turn promoted the rapid generation of catalytically active species. Notably, MWH also significantly improved the N-trideuteromethylation of amines using methanol-d₄, achieving a 95% yield for imipramine-d₃ hydrochloride versus 32% under CH. Molecular dynamics simulations indicated that methanol-d₄ exhibited slower dipole relaxation and enhanced cluster fragmentation under microwave fields, improving catalyst–substrate contact, while kinetic isotope effects stabilized reactive intermediates. These synergistic effects account for the pronounced microwave promotion observed in deuterated systems. Overall, the combination of MWH and cobalt catalysis offers an energy-efficient, waste-minimizing, and environmentally benign strategy for the scalable synthesis of both methylated and deuterated amines. Full article

Alkenylidenecyclopropanes (ACPs) have emerged as versatile and highly reactive building blocks in transition-metal-catalyzed transformations. Their strained cyclopropane framework, combined with an exocyclic alkene, enables diverse bond-activation pathways and promotes efficient cycloaddition reactions. In recent years, ACPs have been widely developed as three-carbon synthons in a variety of higher-order cycloadditions. This review provides a systematic overview of transition-metal-catalyzed ACP transformations, focusing on their applications in [3+2], [3+2+2], [3+2+1], [4+3], and [4+3+2] cycloaddition reactions with reaction partners such as alkenes, alkynes, carbonyl compounds, imines, dienes, and carbon monoxide. Particular attention is given to mechanistic aspects, including cyclopropane ring-opening processes and the formation of key metal–carbene and π-allyl intermediates that govern reactivity and selectivity. Factors influencing regioselectivity, stereoselectivity, and catalyst design are also discussed. The synthetic potential of ACP chemistry is illustrated through representative applications in the total synthesis of complex natural products, such as pyrovellerolactone and (+)-zizaene. Overall, this review highlights recent advances in ACP-based cycloaddition strategies and emphasizes their growing significance in modern synthetic chemistry. Full article

Phenazine derivatives are promising metal-free chromophores with strong redox and photophysical properties, yet their use in photocatalytic hydrogenation remains limited. Here, we report a homogeneous phenazine-based system for the visible-light-driven hydrogenation of nitroarenes under mild conditions. Using nitrobenzene as a model substrate and triethanolamine as a sacrificial hydrogen source, the photocatalyst achieved aniline yields of up to 81% after 12 h of irradiation at 390 nm. Systematic variation in reaction parameters revealed that catalyst structure, solvent, and light wavelength strongly influence performance. Kinetic analysis indicated that prolonged irradiation reduces overall yield due to the reconversion of reactive intermediates. The system exhibited higher efficiency toward nitroarenes bearing electron-withdrawing groups, while aliphatic nitro compounds underwent only partial reduction. Mechanistic studies using UV–Vis, fluorescence, and EPR spectroscopy confirmed the formation of persistent radical species and supported a stepwise electron and proton transfer mechanism. This work showcases the potential of phenazine-based photocatalysts as metal-free platforms for nitroarene reduction under visible light. Full article

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are central regulators of monocyte and macrophage biology, shaping their survival, differentiation, migration, and effector functions. In monocytes and macrophages, ROS and RNS arise from endogenous sources, such as mitochondria, NADPH oxidases, and myeloperoxidase, and from exogenous stimuli including pathogens, damaged tissues, and environmental oxidants. These reactive intermediates converge on redox-sensitive pathways such as NF-κB, Nrf2/HO-1, mitochondrial ROS signalling, and the NLRP3 inflammasome, thereby integrating metabolic stress with inflammatory activation. Redox balance is a key determinant of macrophage polarization: heightened ROS and RNS production drives pro-inflammatory M1 programs, whereas tightly regulated oxidative signalling supports M2 phenotypes associated with tissue repair and resolution. In chronic inflammatory disorders, notably atherosclerosis, oxidative stress amplifies monocyte recruitment, foam-cell formation, plaque instability, and maladaptive immunometabolic responses. The aim of this review is to recapitulate the major sources and functions of ROS and RNS in monocytes and macrophages and to synthesize current evidence on how these pathways collectively maintain or disrupt immune homeostasis. We further highlight emerging therapeutic strategies, such as NOX inhibitors, mitochondrial-targeted antioxidants, and Nrf2 activators, that seek to restore redox balance and offer promising avenues for the treatment of cardiovascular and immune-mediated diseases. Full article

The commercialization of V-based catalysts for the selective catalytic reduction of NOx by NH₃ (NH₃-SCR) is hindered by their narrow operating temperature window, insufficient low-temperature (LT) activity, and severe SO₂-to-SO₃ oxidation. To bridge this gap, we herein introduced Nb and hexagonal BN into a VW/TiO₂ system to simultaneously enhance its LT SCR activity, suppress undesired side reactions, and improve durability. Nb incorporation promoted V⁵⁺/V⁴⁺ redox cycling and enhanced lattice oxygen mobility, thus reducing the apparent activation energy and suppressing SO₂ oxidation at elevated temperatures. However, excessive Nb loading induced NH₃ oxidation and N₂O formation. This drawback was mitigated by introducing BN as a dispersion promoter, which helped secure high catalytic performance at a reduced Nb content. The VWNb/Ti-BN catalyst achieved superior NOx conversion and N₂ selectivity over a wide temperature range and benefited from notably suppressed NH₃ oxidation and SO₂-to-SO₃ oxidation. Kinetic analysis revealed that Nb primarily lowered the reaction energy barrier via redox property enhancement, whereas BN accelerated surface reaction turnover by stabilizing and dispersing active acidic sites, markedly increasing the turnover frequency without reducing the activation energy. In situ spectroscopic analysis confirmed the accelerated consumption of adsorbed NH₃ species and enhanced formation of reactive NOx intermediates, indicating SCR pathway enhancement. After aging in the presence of SO₂ and H₂O, the best-performing honeycomb-type monolithic catalyst retained and NOx conversion of >80%, demonstrating excellent long-term durability under practical conditions. A composition-aware machine learning model based on log-ratio-transformed variables quantitatively identified the synergistic balance among V, Nb, W, BN, and TiO₂ as the dominant factor governing LT SCR performance. Thus, this work provides valuable mechanistic insights and a strategy for designing wide-temperature-window SCR catalysts with improved activity, selectivity, and resistance to sulfur poisoning. Full article

Background: Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation that contributes to cardiometabolic complications. While diabetes duration reflects cumulative metabolic exposure, its relationship with systemic inflammatory burden remains insufficiently defined. We aimed to investigate inflammatory patterns across diabetes duration and to explore their metabolic and cardio–renal correlates. Methods: This real-world cross-sectional study included 250 adults with T2DM. Diabetes duration was analyzed both continuously and across four predefined strata (0–4, 5–9, 10–14, and ≥15 years). Inflammatory burden was assessed using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Given the skewed distribution of CRP, log-transformed CRP was used in regression analyses. Nonlinear associations were evaluated using quadratic regression models. This approach was selected because preliminary descriptive analyses suggested a non-monotonic relationship between diabetes duration and CRP levels. Inclusion of a quadratic term allowed formal testing of a potential curvilinear association between diabetes duration and inflammatory burden. Spearman correlations were performed to assess associations with metabolic, renal, and cardiovascular variables. Results: CRP showed a nonlinear cross-sectional association across diabetes duration strata. Median CRP values were higher in early (0–4 years: 0.62 mg/L) and long-standing diabetes (≥15 years: 0.77 mg/L) compared with intermediate-duration groups (p = 0.063). Quadratic regression confirmed a U-shaped relationship (adjusted β_duration = −0.079, p < 0.001; β_duration² = 0.0027, p < 0.001; R² = 0.326). ESR differed significantly across duration strata (p = 0.002), with the highest levels observed in long-standing diabetes. CRP correlated positively with BMI (ρ = 0.151; p = 0.017) and triglyceride-to-HDL ratio (ρ = 0.215; p < 0.001), but not with HbA1c. Both CRP and ESR were more strongly associated with functional CKD (ρ = 0.350 and 0.429, respectively; p < 0.001) than with ASCVD. Conclusions: Inflammatory burden in T2DM shows a nonlinear cross-sectional pattern across diabetes duration, characterized by elevated levels in early and long-standing disease. Systemic inflammation appears more closely linked to renal dysfunction than to established cardiovascular disease. These findings support a cardio–renal–inflammatory axis in which prolonged diabetes exposure contributes to renal decline, which in turn amplifies systemic inflammatory activation. Full article

Diabetic cardiomyopathy (DbCM) is an important contributor to heart failure (HF) in diabetes, occurring independently of other cardiovascular risk factors. Accumulating evidence demonstrates that cardiac lipotoxicity is a key driver of the onset and progression of DbCM and HF. Myocardial lipid homeostasis is coordinated by multiple transcriptional regulations, signaling pathway activation, and endoplasmic reticulum-mediated management involved in lipid metabolism. In DbCM, unbalanced fatty acid (FA) influx, handling, storage, and utilization initiates lipid overload, accumulation of toxic lipid intermediates (e.g., diacylglycerols and ceramides), and activation of maladaptive response. Notably, these lipid intermediates amplify reactive oxygen species (ROS) generation, which serves as a critical link between lipotoxic signaling and mitochondrial dysfunction by promoting electron leak, mitochondrial damage, and activation of inflammatory and cell-death pathways. These processes converge on adverse remodeling and contractile impairment, accelerating DbCM progression. This review integrates mechanistic and translational evidence linking dysregulated lipid handling to DbCM and discusses the potential therapeutic strategies that target lipid abnormalities. Full article

Background/Objectives: The widespread use of mupirocin and fusidic acid for the treatment and decolonization of Staphylococcus aureus (SA) skin infections has led to a rapid emergence of resistant strains, limiting the effectiveness of the few topical agents currently available for clinical use. Methods: In this study, we evaluate Fe(tropo)₃, a neutral and lipophilic iron(III)–tropolone complex, as a non-antibiotic topical antimicrobial candidate for the management of drug-resistant SA skin and soft tissue infections. Results: Fe(tropo)₃ exhibits potent in vitro activity against methicillin-susceptible SA, methicillin-resistant SA (MRSA), vancomycin-intermediate SA, and strains with high-level resistance to mupirocin and fusidate, with minimum inhibitory concentrations of 2 µg/mL across all tested isolates. The compound effectively penetrates bacterial cells, induces intracellular iron accumulation, and triggers dose-dependent reactive oxygen species generation, resulting in rapid bacterial killing and significant antibiofilm activity. Importantly, Fe(tropo)₃ shows a slower development of resistance compared with ciprofloxacin and displays synergistic activity with oxacillin against MRSA. When formulated as a 1% topical ointment, Fe(tropo)₃ significantly reduces bacterial burden in a murine excisional wound infection model, achieving a 98% ± 1% reduction in SA load without detectable hemolysis or skin irritation. Conclusions: These pilot study results support Fe(tropo)₃ as a clinically relevant, mechanism-distinct topical antimicrobial with potential utility in settings where resistance to existing topical antibiotics compromises standard care. Full article

Background/Objectives: Systemic inflammatory markers are increasingly recognized as prognostic indicators in metastatic colorectal cancer (mCRC), demonstrating significant associations with survival outcomes. The aim of this study was to evaluate the prognostic value of the Aarhus composite biomarker score (ACBS) in patients with metastatic colorectal cancer and to introduce the modified ACBS as a laboratory-based prognostic tool in mCRC. Methods: The Aarhus Composite Biomarker Score was calculated using serum albumin, C-reactive protein (CRP), neutrophil count, lymphocyte count, and hemoglobin levels. The modified Aarhus Composite Biomarker Score-1 (mACBS-1) stratified patients into three prognostic groups: favorable, intermediate, and poor risk. The simplified modified Aarhus Composite Biomarker Score-2 (mACBS-2) categorized patients into two prognostic groups (low vs. high risk). Survival analyses were performed using the Kaplan–Meier method, and prognostic factors were evaluated using Cox regression analysis. Results: The median overall survival (OS) was 35 months (95% CI: 29.38–40.62). Stratification by mACBS-1 revealed median OS values of 47, 30, and 14 months for favorable-, intermediate-, and poor-risk groups, respectively (p = 0.002). Similarly, mACBS-2 distinguished two prognostic groups, with median OS of 47 months in the favorable-risk group and 30 months in the poor-risk group (p = 0.001). In multivariable analysis, ACBS remained an independent predictor of overall survival, with three abnormal biomarkers conferring a significantly increased mortality risk (HR 4.61, 95% CI 2.17–9.82, p < 0.001). Similarly, poor-risk classification by mACBS-1 (HR 3.36, 95% CI 1.58–7.12, p = 0.002) and mACBS-2 (HR 2.05, 95% CI 1.29–3.26, p = 0.002) was independently associated with worse survival. Conclusions: The ACBS and its modified versions (mACBS-1 and mACBS-2) are simple, laboratory-based prognostic tools with independent predictive value for survival in metastatic colorectal cancer. Its clinical use may support improved risk stratification and individualized patient management. Full article

Background/Aims: Sepsis as an acute cause of liver dysfunction is associated with high mortality. Routine infection/inflammation markers—C-reactive-protein (CRP), procalcitonin (PCT), and leukocyte count (LeuC)—are frequently used for risk stratification in septic patients. This study aimed to evaluate these markers as predictors of short-term and 12-month mortality in septic patients with distinct liver dysfunction phenotypes. Methods: This single-center retrospective pilot analysis involved adults with sepsis and varying degrees of liver dysfunction—acute liver failure (ALF), acute-on-chronic liver failure (ACLF), or acute-on-cirrhosis (ACOC)—treated in intermediate or intensive care units between 2016 and 2017. At sepsis onset, patients were categorized into ACOC, ACLF, and ALF groups. Only patients with recorded CRP, PCT, and LeuC measurements 24 h before, on the day of, and 24/48 h after sepsis onset were included in the analysis. Associations with in-hospital and 12-month mortality were analyzed using Firth bias-reduced logistic regression, ROC analysis, and internal validation by bootstrapping and cross-validation. Results: 49 patients were included (ACOC n = 21; ACLF n = 20; ALF n = 8). In-hospital and 12-month mortality rates were 34.7% and 61.2%, respectively, with the highest long-term mortality observed in the ACOC group (76.2%). In the ACOC group, PCT 24 h before sepsis onset independently predicted in-hospital mortality (OR ~5 per PCT doubling; AUC 0.94), with an optimal rule-in cut-off of 1.0 ng/mL (specificity 1.00, PPV 1.00). PCT was not predictive in ACLF/ALF, and CRP/LeuC offered limited prognostic value. Conclusions: In this hypothesis-generating analysis, PCT 24 h before sepsis onset shows a phenotype-specific association with early mortality in ACOC. Larger, prospective multicenter studies are needed to validate PCT-guided risk stratification. Full article

Neuroinflammation mediated by reactive microglia, the immune cells of the brain, contributes to numerous neuropathologies. Damage-associated molecular patterns (DAMPs), released from stressed or damaged cells, are implicated in neuroinflammation. Succinate, a tricarboxylic acid cycle intermediate, can accumulate intracellularly and be released into the extracellular space where it may function as a DAMP-like molecule. However, its specific roles in central nervous system (CNS) neuroimmune responses, particularly when acting extracellularly, remain largely unexplored. This study utilizes cell membrane-impermeable disodium succinate to model extracellular action and cell-permeable diethyl succinate to assess the intracellular activity of this metabolite in cell culture models. We demonstrate that extracellular disodium succinate significantly reduces the secretion of pro-inflammatory cytokines tumor necrosis factor-α (TNF) and interleukin (IL)-6, and lowers neurotoxic and phagocytic activities of immune-stimulated BV-2 murine microglia. It also rescues lipopolysaccharide (LPS)-induced decreases in mitochondrial respiration in human peripheral blood mononuclear cells (PBMCs) used as microglia models, which correlates with its actions on phagocytosis. In contrast, while intracellular diethyl succinate reduces TNF and IL-6 secretion, it does not reduce BV-2 microglia toxicity towards murine NSC-34 neuronal cells, indicating location-dependent effects. These results support extracellular succinate as a novel CNS DAMP with a predominantly anti-inflammatory action on microglia. Full article

Chromium (Cr) remains a significant environmental health concern, with exposure mainly through ingestion and inhalation. Its toxicological profile is driven by oxidation state: trivalent chromium [Cr(III)] shows low bioavailability, whereas hexavalent chromium [Cr(VI)] is highly bioavailable, crosses cell membranes, and generates reactive intermediates associated with oxidative and genotoxic effects. Several studies have highlighted the assessment of chromium exposure, particularly Cr(III) and Cr(VI), across different biological matrices as a key approach for accurate exposure characterization. This review synthesizes experimental and epidemiological evidence regarding urinary chromium (uCr) as a biomarker of exposure, alongside advances in analytical techniques and the emerging exposome framework. Although widely used due to non-invasive sampling and suitability for large studies, uCr primarily reflects recent exposure (<48 h), exhibits high intra- and inter-individual variability, and lacks routine Cr(VI)/Cr(III) speciation, limiting its value for low-level environmental exposure. Unlike urinary or whole blood chromium, chromium in red blood cells (RBCs) is specific to Cr(VI) exposure, since in vitro studies reveal selective, donor-independent accumulation of hexavalent chromium in RBCs. However, the current literature is primarily concerned with sampling strategies, pre-treatment procedures, and analytical validation, with comparatively little consideration given to chromium speciation and species interconversion in biological matrices, despite their essential significance for exposure assessment and toxicological interpretation. Full article

Our recent work has focused on red light-mediated photoreduction of p-benzoquinones and both o-, and p-naphthoquinones using methylene blue and the chlorophyll metabolite, pheophorbide A as photosensitizers. Photoreduction of biologically relevant quinones mimics photoreduction of plastoquinone by chlorophyll in photosynthesis. We examined photo-oxidation and photoreduction reactions of catechols because their oxidation to o-quinones by reactive oxygen species is implicated in protein damage in neurodegeneration. Photo-oxidation of catecholamines including dopamine, epinephrine and norepinephrine required red light, methylene blue or pheophorbide A, and molecular oxygen. Their cyclized oxidation products, aminochrome, adrenochrome and noradrenochrome, were detected by UV/visible spectroscopy. Hydrogen peroxide was generated during photo-oxidation by singlet oxygen-dependent oxidation of catecholamines. Inclusion of tertiary amine electron donors decreased cyclized products but did not affect hydrogen peroxide yield consistent with concurrent photo-oxidation followed by photoreduction of the o-quinone intermediate. Unreacted dopamine and norepinephrine were quantified using 3-hydroxyphenyl boronic acid following photochemical reactions. Dopamine and norepinephrine boronate esters absorb at 417 and 550 nm. Photo-oxidation of dihydroxycaffeic acid and dihydroxyphenyl acetic acid was also evaluated by detecting their boronate esters at 475 nm. We hypothesize that photoreduction of transient o-quinones by the combination of red light and dietary chlorophyll metabolites may be a path to limit protein damage and to recycle catechol antioxidants. Full article

Low-saturated hydraulic conductivity covers (LSHCC) or hydraulic barriers are one of the reclamation techniques used to control the acid mine drainage generation (AMD). These covers are intended to limit the infiltration of water into reactive tailings. Compacted clays are among the materials used as LSHCC. The performance of clay-based hydraulic barriers can be affected by their geotechnical and hydrogeological properties. Freeze–thaw cycles can increase their saturated hydraulic conductivity (k_sat). However, these effects can be minimized by adding amendments. To evaluate the performance of these clay-based covers, four field experimental cells were built. The first one simulates a cover composed entirely of clay, the second a clay–silt mixture, the third a clay–sand mixture and the last two layers of clay with an intermediate layer of silt. Each cell has been equipped with a monitoring station with continuous measurements of volumetric water content, suction and temperature. In situ permeability tests were also conducted to assess field hydraulic conductivity. Numerical simulations were also conducted to evaluate the water balance for each cover scenario. The laboratory results showed low-saturated hydraulic conductivity values meeting waterproofing criteria, whereas field measurements and calibrated model values were consistently higher and exceeded the waterproofing criteria. Infiltration monitoring indicated that 15 to 40% of precipitation infiltrated the covers, with possible overestimation due to preferential flow. Discrepancies between laboratory and field-saturated hydraulic conductivity values were mainly attributed to inadequate compaction, unfavorable weather conditions, and excessive water content during cover installation. Variations in saturated hydraulic conductivity over time were generally within statistical variability, although differences among cells and responses to wetting–drying cycles highlight the influence of construction conditions on field performance. Full article